Maria Cristina MENZIANI - personale UniMoRe

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Maria Cristina MENZIANI

Professore Ordinario
Dipartimento di Scienze Chimiche e Geologiche - Sede Dipartimento di Scienze Chimiche e Geologiche

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Pubblicazioni

2024 - Quantum-Chemistry Study of the Hydrolysis Reaction Profile in Borate Networks: A Benchmark [Articolo su rivista]
Muniz-Miranda, Francesco; Occhi, Leonardo; Fontanive, Francesco; Menziani, Maria Cristina; Pedone, Alfonso
abstract

This investigation involved an ab initio and Density Functional Theory (DFT) analysis of the hydrolysis mechanism and energetics in a borate network. The focus was on understanding how water molecules interact with and disrupt the borate network, an area where the experimental data are scarce and unreliable. The modeled system consisted of two boron atoms, bridging oxygen atoms, and varying numbers of water molecules. This setup allows for an exploration of hydrolysis under different environmental conditions, including the presence of OH− or H+ ions to simulate basic or acidic environments, respectively. Our investigation utilized both ab initio calculations at the MP2 and CCSD(T) levels and DFT with a range of exchange–correlation functionals. The findings indicate that the borate network is significantly more susceptible to hydrolysis in a basic environment, with respect to an acidic or to a neutral pH setting. The inclusion of explicit water molecules in the calculations can significantly affect the results, depending on the nature of the transition state. In fact, some transition states exhibited closed-ring configurations involving water and the boron–oxygen–boron network; in these cases, there were indeed more water molecules corresponding to lower energy barriers for the reaction, suggesting a crucial role of water in stabilizing the transition states. This study provides valuable insights into the hydrolysis process of borate networks, offering a detailed comparison between different computational approaches. The results demonstrate that the functionals B3LYP, PBE0, and wB97Xd closely approximated the reference MP2 and CCSD(T) calculated reaction pathways, both qualitatively in terms of the mechanism, and quantitatively in terms of the differences in the reaction barriers within the 0.1–0.2 eV interval for the most plausible reaction pathways. In addition, CAM-B3LYP also yielded acceptable results in all cases except for the most complicated pathway. These findings are useful for guiding further computational studies, including those employing machine learning approaches, and experimental investigations requiring accurate reference data for hydrolysis reactions in borate networks.

2023 - Alginate Beads Containing Cerium-Doped Mesoporous Glass and Curcumin: Delivery and Stabilization of Therapeutics [Articolo su rivista]
Carrozza, Debora; Malavasi, Gianluca; Ferrari, Erika; Menziani, Maria Cristina
abstract

: Cancer is a leading cause of death worldwide, its genesis and progression are caused by homeostatic errors, and reactive oxygen species play a major role in promoting aberrant cancer homeostasis. In this scenario, curcumin could be an interesting candidate due to its versatile antioxidant, anti-inflammatory, anti-tumor, anti-HIV, and anti-infection properties. Nonetheless, the major problem related to its use is its poor oral bioavailability, which can be overcome by encapsulating it into small particles, such as hydrogel beads containing mesoporous silica. In this work, various systems have been synthesized: starting from mesoporous silica glasses (MGs), cerium-containing MGs have been produced; then, these systems have been loaded with 4 to 6% of curcumin. Finally, various MGs at different compositions have been included in alginate beads. In vitro studies showed that these hybrid materials enable the stabilization and effective delivery of curcumin and that a synergic effect can be achieved if Ce3+/Ce4+ and curcumin are both part of the beads. From swelling tests, it is possible to confirm a controlled curcumin release compartmentalized into the gastrointestinal tract. For all beads obtained, a curcumin release sufficient to achieve the antioxidant threshold has been reached, and a synergic effect of cerium and curcumin is observed. Moreover, from catalase mimetic activity tests, we confirm the well-known catalytic activity of the couple Ce3+/Ce4+. In addition, an extremely good radical scavenging effect of curcumin has been demonstrated. In conclusion, these systems, able to promote an enzymatic-like activity, can be used as drug delivery systems for curcumin-targeted dosing.

2023 - Can DFT Calculations Provide Useful Information for SERS Applications? [Articolo su rivista]
Muniz-Miranda, Maurizio; Muniz-Miranda, Francesco; Menziani, Maria Cristina; Pedone, Alfonso
abstract

: Density functional theory (DFT) calculations allow us to reproduce the SERS (surface-enhanced Raman scattering) spectra of molecules adsorbed on nanostructured metal surfaces and extract the most information this spectroscopy is potentially able to provide. The latter point mainly concerns the anchoring mechanism and the bond strength between molecule and metal as well as the structural and electronic modifications of the adsorbed molecule. These findings are of fundamental importance for the application of this spectroscopic technique. This review presents and discusses some SERS-DFT studies carried out in Italy as a collaboration between the universities of Modena and Reggio-Emilia and of Florence, giving an overview of the information that we can extract with a combination of experimental SERS spectra and DFT modeling. In addition, a selection of the most recent studies and advancements on the DFT approach to SERS spectroscopy is reported with commentary.

2023 - Erratum for a new self‐consistent empirical potential model for multicomponent borate and borosilicate glasses (Journal of the American Ceramic Society, (2022), 105, 12, (7254-7271), 10.1111/jace.18681) [Articolo su rivista]
Bertani, M.; Pallini, A.; Lodesani, F.; Cocchi, M.; Menziani, M. C.; Pedone, A.
abstract

The manuscript contains a mistake in Equation (6) and an erroneous value of the B-ij term of B-O interaction in Table 2. An additional sentence is needed in paragraph 2.2. These errata acknowledge and correct the mistakes and add the needed information. The corrections do not lead to any changes in the results, discussion, and conclusion.

2023 - Evidence of Multiple Crystallization Pathways in Lithium Disilicate: A Metadynamics Investigation [Articolo su rivista]
Lodesani, F.; Menziani, M. C.; Urata, S.; Pedone, A.
abstract

Metadynamics simulations driven by using two X-ray diffraction peaks identified three alternative crystallization pathways of the lithium disilicate crystal from the melt. The most favorable one passes through the formation of disordered layered structures undergoing internal ordering in a second step. The second pathway involves the formation of phase-separated structures composed of nuclei of beta-cristobalite crystals surrounded by lithium -rich phases in which metasilicate chains are formed. The conversion of these structures to the stable lithium disilicate crystal involves an intermediate structure whose silicate layers are connected by silicate rings with the energy barrier of 2.5 kJ/mol per formula unit (f.u.). The third pathway is highly unlikely because of the huge energy barrier involved (20 kJ/mol per f.u.). This path also involves the passage through a phase-separated structure of an indefinite silica region surrounded mainly by amorphous lithium oxide.

2022 - A new self-consistent empirical potential model for multicomponent borate and borosilicate glasses [Articolo su rivista]
Bertani, M.; Pallini, A.; Cocchi, M.; Menziani, M. C.; Pedone, A.
abstract

A new self-consistent empirical potential model based on the BMP potential [Bertani et al., Phys. Rev. Mat. 5 (2021) 045602] has been developed for the simulation of multicomponent borate and borosilicate glasses. We exploited the Bayesian optimization approach to create a set of parameters for the B–O interaction, which depends on the glass composition, and in particular on the R = ([A2O]+[AEO])/[B2O3] (A = alkaline and AE alkaline-earth ions) and K = [SiO2]/[B2O3] ratios. The obtained force field (FF) has been applied to several borate and borosilicate glass series containing, as modifier oxide, Na2O, Li2O, CaO, and MgO and tested on experimental data, such as the fraction of BO4 (N4), density, non-bridging oxygen speciation, neutron diffraction spectra, 11B, 29Si, and 17O magic angle spinning nuclear magnetic resonance. A comparison with other interatomic potentials available in literature has also been performed. The results show that the FF reproduces well almost all the abovementioned properties, showing excellent agreement with experimental data in a wide range of compositions.

2022 - Biasing crystallization in fused silica: An assessment of optimal metadynamics parameters [Articolo su rivista]
Lodesani, F.; Menziani, M. C.; Urata, S.; Pedone, A.
abstract

Metadynamics (MetaD) is a useful technique to study rare events such as crystallization. It has been only recently applied to study nucleation and crystallization in glass-forming liquids such as silicates, but the optimal set of parameters to drive crystallization and obtain converged free energy surfaces is still unexplored. In this work, we systematically investigated the effects of the simulation conditions to efficiently study the thermodynamics and mechanism of crystallization in highly viscous systems. As a prototype system, we used fused silica, which easily crystallizes to β-cristobalite through MetaD simulations, owing to its simple microstructure. We investigated the influence of the height, width, and bias factor used to define the biasing Gaussian potential, as well as the effects of the temperature and system size on the results. Among these parameters, the bias factor and temperature seem to be most effective in sampling the free energy landscape of melt to crystal transition and reaching convergence more quickly. We also demonstrate that the temperature rescaling from T > Tm is a reliable approach to recover free energy surfaces below Tm, provided that the temperature gap is below 600 K and the configurational space has been properly sampled. Finally, albeit a complete crystallization is hard to achieve with large simulation boxes, these can be reliably and effectively exploited to study the first stages of nucleation.

2022 - DFT and TD-DFT Study of the Chemical Effect in the SERS Spectra of Piperidine Adsorbed on Silver Colloidal Nanoparticles [Articolo su rivista]
Muniz-Miranda, Francesco; Pedone, Alfonso; Menziani, Maria Cristina; Muniz-Miranda, Maurizio
abstract

2021 - Computational insight on the interaction of common blood proteins with gold nanoparticles [Articolo su rivista]
Tavanti, F.; Menziani, M. C.
abstract

Protein interactions with engineered gold nanoparticles (AuNPs) and the consequent formation of the protein corona are very relevant and poorly understood biological phenomena. The nanoparticle coverage affects protein binding modalities, and the adsorbed protein sites influence interactions with other macromolecules and cells. Here, we studied four common blood proteins, i.e., hemoglobin, serum albumin, α1-antiproteinase, and complement C3, interacting with AuNPs covered by hydrophobic 11-mercapto-1-undecanesulfonate (MUS). We use Molecular Dynamics and the Martini coarse−grained model to gain quantitative insight into the kinetics of the interaction, the physico-chemical characteristics of the binding site, and the nanoparticle adsorption capacity. Results show that proteins bind to MUS−capped AuNPs through strong hydrophobic interactions and that they adapt to the AuNP surfaces to maximize the contact surface, but no dramatic change in the secondary structure of the proteins is observed. We suggest a new method to calculate the maximum adsorption capacity of capped AuNPs based on the effective surface covered by each protein, which better represents the realistic behavior of these systems.

2021 - Development and Application of a ReaxFF Reactive Force Field for Cerium Oxide/Water Interfaces [Articolo su rivista]
Brugnoli, L.; Menziani, M. C.; Urata, S.; Pedone, A.
abstract

Ceria (CeO2) is a well-known catalytic oxide with many environmental, energy production, and industrial applications, most of them involving water as a reactant, byproduct, solvent, or simple spectator. In this work, we parameterized a Ce/O/H ReaxFF for the study of ceria and ceria/water interfaces. The parameters were fitted to anab initiotraining set obtained at the DFT/PBE0 level, including the structures, cohesive energies, and elastic properties of the crystalline phases Ce, CeO2, and Ce2O3; the O-defective structures and energies of vacancy formation on CeO2bulk and CeO2(111) surface, as well as the absorption and reaction energies of H2and H2O molecules on CeO2(111). The new potential reproduced reasonably well all the fitted properties as well as the relative stabilities of the different ceria surfaces, the oxygen vacancies formation, and the energies and structures of associative and dissociative water molecules on them. Molecular dynamics simulations of the liquid water on the CeO2(111) and CeO2(100) surfaces were carried out to study the coverage and the mechanism of water dissociation. After equilibration, on average, 35% of surface sites of CeO2(111) are hydroxylated whereas 15% of them are saturated with molecular water associatively adsorbed. As for the CeO2(100) surface, we observed that water preferentially dissociates covering 90% of the available surface sites in excellent agreement with recent experimental findings.

2021 - Disclosing the interaction of gold nanoparticles with aβ(1–40) monomers through replica exchange molecular dynamics simulations [Articolo su rivista]
Tavanti, F.; Pedone, A.; Menziani, M. C.
abstract

Amyloid-β aggregation is one of the principal causes of amyloidogenic diseases that lead to the loss of neuronal cells and to cognitive impairments. The use of gold nanoparticles treating amyloidogenic diseases is a promising approach, because the chemistry of the gold surface can be tuned in order to have a specific binding, obtaining effective tools to control the aggregation. In this paper, we show, by means of Replica Exchange Solute Tempering Molecular Simulations, how electrostatic interactions drive the absorption of Amyloid-β monomers onto citrates-capped gold nanoparticles. Importantly, upon binding, amyloid monomers show a reduced propensity in forming β-sheets secondary structures that are characteristics of mature amyloid fibrils.

2021 - Exploring Translocator Protein (TSPO) Medicinal Chemistry: An Approach for Targeting Radionuclides and Boron Atoms to Mitochondria [Articolo su rivista]
Giordani, A.; Menziani, M. C.; Moresco, R. M.; Matarrese, M.; Paolino, M.; Saletti, M.; Giuliani, G.; Anzini, M.; Cappelli, A.
abstract

Translocator protein 18 kDa [TSPO or peripheral-type benzodiazepine receptor (PBR)] was identified in the search of binding sites for benzodiazepine anxiolytic drugs in peripheral regions. In these areas, binding sites for TSPO ligands were recognized in steroid-producing tissues. TSPO plays an important role in many cellular functions, and its coding sequence is highly conserved across species. TSPO is located predominantly on the membrane of mitochondria and is overexpressed in several solid cancers. TSPO basal expression in the CNS is low, but it becomes high in neurodegenerative conditions. Thus, TSPO constitutes not only as an outstanding drug target but also as a valuable marker for the diagnosis of a number of diseases. The aim of the present article is to show the lesson we have learned from our activity in TSPO medicinal chemistry and in approaching the targeted delivery to mitochondria by means of TSPO ligands.

2021 - Exploring the crystallization path of lithium disilicate through metadynamics simulations [Articolo su rivista]
Lodesani, F.; Tavanti, F.; Menziani, M. C.; Maeda, K.; Takato, Y.; Urata, S.; Pedone, A.
abstract

Understanding the crystallization mechanism in silica-based materials is of paramount importance to comprehend geological phenomena and to design novel materials for a variety of technological and industrial applications. In this work, we show that metadynamics simulations can effectively overcome a large energy barrier to crystallize from viscous oxide glass melts and can be used to identify the melt-to-crystal transition path of the lithium disilicate system. The accelerated atomistic simulation revealed of a two-step mechanism of the nanoscale crystal formation. First, a partially layered silica embryo appeared, and then a more ordered crystalline layer with size larger than the critical nucleus size was formed. Subsequently, lithium ions piled up around the silicate layer and triggered stacking of adjacent silicate layers, which eventually built a perfect crystal. Contrarily to previous hypotheses, no lithium metasilicate crystal was observed as a precursor of the homogeneous crystallization of lithium disilicate.

2021 - Improved empirical force field for multicomponent oxide glasses and crystals [Articolo su rivista]
Bertani, M.; Menziani, M. C.; Pedone, A.
abstract

In this paper, the self-consistent PMMCS force fields (FFs) [Pedone et al., J. Phys. Chem. B 110, 11780 (2006)10.1021/jp0611018] widely used for the simulation of a large variety of silicates, aluminosilicate and phosphate crystals, and multicomponent oxide glasses have been revised and improved by the inclusion of two types of three-body interactions acting between T-O-T bridges (T=Si and P) and network former-network former repulsive interactions. The FFs named Bertani-Menziani-Pedone (BMP)-harm and BMP-shrm better reproduce the T-O-T bond angle distributions (BADs) and network former-oxygen distances. Consequently, the prediction of Qn distributions (Q stands for quaternary species, and n is the number of bridging oxygens around it), neutron total distribution functions, solid-state nuclear magnetic resonance spectra of spin active nuclei (Si29, O17, P31, Al27), and the density have also been hugely improved with respect to the previous version of our FF. These results also highlight the strong correlation between the T-O-T BADs and the other short and intermediate structural properties in oxide glasses, which have been largely neglected in the past. In addition to the improvement of the structure, the FF has been revealed to reproduce well the ionic conductivity in mixed alkali aluminosilicate glasses and the elastic properties. The systematic comparison with other interatomic potential models, including the polarizable core-shell model, carried out in this paper showed that our potential model is more balanced and effective for simulating a vast family of crystalline and amorphous oxide-based systems.

2021 - Novel Pet-Degrading Enzymes: Structure-Function from a Computational Perspective [Articolo su rivista]
Berselli, A.; Ramos, M. J.; Menziani, M. C.
abstract

The bacterium strain Ideonella sakaiensis 201-F6 is able to hydrolyze low-crystallinity PET films at 30 °C due to two enzymes named PETase and MHETase. Since its discovery, many efforts have been dedicated to elucidating the structure and features of those two enzymes, and various authors have highlighted the necessity to optimize both the substrate binding site and the global structure in order to enhance the stability and catalytic activity of these PET biocatalysts so as to make them more suitable for industrial applications. In this review, the strategies adopted by different research groups to investigate the structure and functionality of both PETase and MHETase in depth are described, emphasizing the advantages provided by the use of computational methods to complement and drive experiments. Subsequently, the modifications implemented with protein engineering are discussed. The versatility of the enzymes secreted by I. sakaiensis enables the prediction that they will find several applications in the disposal of PET debris, encouraging a prioritization of efforts in this prolific research field.

2021 - Toward the understanding of crystallization, mechanical properties and reactivity of multicomponent bioactive glasses [Articolo su rivista]
Pedone, Alfonso; Cannillo, Valeria; Menziani, Maria Cristina
abstract

2020 - Computational insights into the binding of monolayer-capped gold nanoparticles onto amyloid-β fibrils [Articolo su rivista]
Tavanti, F.; Pedone, A.; Menziani, M. C.; Alexander-Katz, A.
abstract

Amyloids-β (Aβ) fibrils are involved in several neurodegenerative diseases. In this study, atomistic molecular dynamics simulations have been used to investigate how monolayer-protected gold nanoparticles interact with Aβ(1-40) and Aβ(1-42) fibrils. Our results show that small gold nanoparticles bind with the external side of amyloid-β fibrils that is involved in the fibrillation process. The binding affinity, studied for both kinds of fibrils as a function of the monolayer composition and the nanoparticle diameter, is modulated by hydrophobic interactions and ligand monolayer conformation. Our findings thus show that monolayer-protected nanoparticles are good candidates to prevent fibril aggregation and secondary nucleation or to deliver drugs to specific fibril regions.

2020 - Disclosing crystal nucleation mechanism in lithium disilicate glass through molecular dynamics simulations and free-energy calculations [Articolo su rivista]
Lodesani, F.; Menziani, M. C.; Maeda, K.; Takato, Y.; Urata, S.; Pedone, A.
abstract

Unraveling detailed mechanism of crystal nucleation from amorphous materials is challenging for both experimental and theoretical approaches. In this study, we have examined two methods to understand the initial stage of crystal precipitation from lithium disilicate glasses using molecular dynamics simulations. One of the methods is a modified exploring method to find structurally similar crystalline clusters in the glass models, enabling us to find three different embryos, such as Li2Si2O5 (LS2), Li2SiO3 (LS) and Li3PO4 (LP), in the 33Li2O·66SiO2·1P2O5 glass (LS2P1), in which P2O5 is added as a nucleating agent. Interestingly, LS2 and LP crystals were found inside the LS2P1 glass while LS crystal appeared on the glass surface, which agrees with experimental observations. The other method is free energy calculation using a subnano-scale spherical crystal embedded in the glass model. This method, which we called Free-Energy Seeding Method (FESM), allows us to evaluate free energy change as a function of crystal radius and to identify critical size of the crystal precipitation. The free energy profiles for LS and LS2 crystal nuclei in the LS2 glass models possess maximum energy at a critical radius as expected by classical nucleation theory. Furthermore, the critical radius and the energy barrier height agree well with recent experimental investigation, proving the applicability of this method to design glass–ceramics by atomistic modeling.

2020 - Insights into the effect of curcumin and (–)-epigallocatechin-3-gallate on the aggregation of aβ(1–40) monomers by means of molecular dynamics [Articolo su rivista]
Tavanti, F.; Pedone, A.; Menziani, M. C.
abstract

In this study, we compared the effects of two well-known natural compounds on the early step of the fibrillation process of amyloid-β (1–40), responsible for the formation of plaques in the brains of patients affected by Alzheimer’s disease (AD). The use of extensive replica exchange simulations up to the µs scale allowed us to characterize the inhibition activity of (–)-epigallocatechin-3-gallate (EGCG) and curcumin (CUR) on unfolded amyloid fibrils. A reduced number of β-strands, characteristic of amyloid fibrils, and an increased distance between the amino acids that are responsible for the intra-and interprotein aggregations are observed. The central core region of the amyloid-β (Aβ(1–40)) fibril is found to have a high affinity to EGCG and CUR due to the presence of hydrophobic residues. Lastly, the free binding energy computed using the Poisson Boltzmann Surface Ares suggests that EGCG is more likely to bind to unfolded Aβ(1–40) fibrils and that this molecule can be a good candidate to develop new and more effective congeners to treat AD.

2020 - O2Activation over Ag-Decorated CeO2(111) and TiO2(110) Surfaces: A Theoretical Comparative Investigation [Articolo su rivista]
Brugnoli, L.; Pedone, A.; Menziani, M. C.; Adamo, C.; Labat, F.
abstract

Periodic spin-polarized hybrid density functional theory calculations have been performed to investigate the reactivity of pristine, O-defective, and Ag-decorated CeO2(111) and TiO2(110) surfaces with a small Ag10 cluster toward O2. The adsorption of O2 and its subsequent dissociation have been studied in order to provide a better understanding of the role of the oxide, the metallic nanoparticle, and their interaction in the reactivity of composite metal/metal oxide materials toward O2, as potential catalysts to this reaction. Structural, energetic, electronic, and vibrational properties of all species involved in the different reaction paths considered have been fully characterized. On the stoichiometric surfaces, Ag10 is oxidized and reduces surface Ce4+/Ti4+ ions, while on the O-defective surfaces, the adhesion of silver is promoted only on CeO2 but unfavored on TiO2. On the other hand, on the silver-free supports, O2 strongly adsorbs at vacancies and preferentially reduces to peroxide. When no O vacancies are considered on the Ag10-decorated supports, the net positive charge on Ag10 actually prevents the adsorption and reduction of O2. Instead, when O vacancies are included, two reaction pathways are observed; oxygen molecules can weakly absorb on the silver cluster as a superoxide moiety or strongly adsorb at the vacancy as peroxide. The dissociation of the O-O bond of the peroxide is favored both from the thermodynamic and kinetic points of view in silver-decorated surfaces, in contrast with the silver-free cases. In addition, Ag10/CeO2 shows higher activity toward the O2 adsorption and dissociation than Ag10/TiO2, which can be related both to the higher ionicity and superior electron storage/release ability of ceria with respect to titania, thus leading to the weakening of the O-O bond and providing lower activation barriers for oxygen reduction. These results deepen the current understanding of the reactivity of metal/metal oxide composites toward O2, especially elucidating how the surface stoichiometry affects the charge state of the metal clusters, and hence the reactivity of these interfaces toward O2, with potential important consequences when such composites are considered for catalytic applications.

2020 - Structural origins of the Mixed Alkali Effect in Alkali Aluminosilicate Glasses: Molecular Dynamics Study and its Assessment [Articolo su rivista]
Lodesani, Federica; Menziani, Maria Cristina; Hijiya, Hiroyuki; Takato, Yoichi; Urata, Shingo; Pedone, Alfonso
abstract

The comprehension of the nonlinear effects provided by mixed alkali effect (MAE) in oxide glasses is useful to optimize glass compositions to achieve specific properties that depend on the mobility of ions, such as the chemical durability, glass transition temperature, viscosity and ionic conductivity. Although molecular dynamics (MD) simulations have already been applied to investigate the MAE on silicates, less effort has been devoted to study such phenomenon in mixed alkali aluminosilicate glasses where alkali cations can act both as modifiers, forming non-bridging oxygens and percolation channels, and as charge compensator of the AlO4− units present in the network. Moreover, the ionic conductivity has not been computed yet; thus, the accuracy of the atomistic simulations in reproducing the MAE on the property is still open to question. In this work, we have validated five major interatomic potentials for the classical MD simulations by modelling the structure, density, glass transition temperature and ionic conductivity for three aluminosilicate glasses, (25 − x)Na2O − x(K2O) − 10(Al2O3) − 65(SiO2) (x = 0, 12.5, 25). It was observed that only the core-shell (CS) polarizable force field well reproduces the experimentally measured MAE on Tg and the ionic conductivity as well as the higher conductivity of single sodium aluminosilicate glass at low temperature and the higher conductivity of single potassium aluminosilicate glass at high temperature. The MAE is related to the suppression of jump events of the alkaline ions between dissimilar sites in the percolation channels consisting of both sodium and potassium ions as in the case of alkaline silicates. The superior reproducibility of the CS potential is originated from the larger and the flexible ring structures due to the smaller Si-O-Si inter-tetrahedra angle, creating appropriate percolation channels for ion conductivity. We also report detailed assessments for using the potential models including the CS potential for investigating MAE on aluminosilicates.

2020 - Unraveling the complexity of amyloid polymorphism using gold nanoparticles and cryo-EM [Articolo su rivista]
Cendrowska, U.; Silva, P. J.; Ait-Bouziad, N.; Muller, M.; Guven, Z. P.; Vieweg, S.; Chiki, A.; Radamaker, L.; Kumar, S. T.; Fandrich, M.; Tavanti, F.; Menziani, M. C.; Alexander-Katz, A.; Stellacci, F.; Lashuel, H. A.
abstract

Increasing evidence suggests that amyloid polymorphism gives rise to different strains of amyloids with distinct toxicities and pathology-spreading properties. Validating this hypothesis is challenging due to a lack of tools and methods that allow for the direct characterization of amyloid polymorphism in hydrated and complex biological samples. Here, we report on the development of 11-mercapto-1-undecanesulfonate-coated gold nanoparticles (NPs) that efficiently label the edges of synthetic, recombinant, and native amyloid fibrils derived from different amyloidogenic proteins. We demonstrate that these NPs represent powerful tools for assessing amyloid morphological polymorphism, using cryogenic transmission electron microscopy (cryo-EM). The NPs allowed for the visualization of morphological features that are not directly observed using standard imaging techniques, including transmission electron microscopy with use of the negative stain or cryo-EM imaging. The use of these NPs to label native paired helical filaments (PHFs) from the postmortem brain of a patient with Alzheimer's disease, as well as amyloid fibrils extracted from the heart tissue of a patient suffering from systemic amyloid light-chain amyloidosis, revealed a high degree of homogeneity across the fibrils derived from human tissue in comparison with fibrils aggregated in vitro. These findings are consistent with, and strongly support, the emerging view that the physiologic milieu is a key determinant of amyloid fibril strains. Together, these advances should not only facilitate the profiling and characterization of amyloids for structural studies by cryo-EM, but also pave the way to elucidate the structural basis of amyloid strains and toxicity, and possibly the correlation between the pathological and clinical heterogeneity of amyloid diseases.

2019 - A DFT approach to the surface-enhanced raman scattering of 4-cyanopyridine adsorbed on silver nanoparticles [Articolo su rivista]
Lopez-Tocon, I.; Valdivia, S.; Soto, J.; Otero, J. C.; Muniz-Miranda, F.; Menziani, Maria Cristina; Muniz-Miranda, M.
abstract

A Surface-Enhanced Raman Scattering (SERS) spectrum of 4-cyanopyridine (4CNPy) was recorded on silver plasmonic nanoparticles and analyzed by using Density Functional Theory (DFT) calculations. Two simple molecular models of the metal–4CNPy surface complex with a single silver cation or with a neutral dimer (Ag+ –4CNPy, Ag2 –4CNPy), linked through the two possible interacting sites of 4CNPy (aromatic nitrogen, N, and nitrile group, CN), were considered. The calculated vibrational wavenumbers and intensities of the adsorbate and the isolated species are compared with the experimental Raman and SERS results. The analysis of the DFT predictions and the experimental data indicates that 4CNPy adsorbs preferentially on neutral/charged active sites of the silver nanoparticles through the nitrogen atom of the aromatic ring with a perpendicular orientation.

2019 - DARPin_9-29-Targeted Mini Gold Nanorods Specifically Eliminate HER2-Overexpressing Cancer Cells [Articolo su rivista]
Proshkina G., Deyev S.; A., Ryabova; Tavanti, Francesco; Menziani, Maria Cristina; R., Cohen; L., Katrivas; A., Kotlyar
abstract

We have demonstrated that designed ankyrin repeat protein (DARPin)_9-29, which specifically targets human epidermal growth factor receptor 2 (HER2), binds tightly to gold mini nanorods (GNRs). Molecular dynamic simulations showed that a single layer of DARPin_9-29 molecules is formed on the surface of the nanorod and that conjugation with the nanorod does not involve the protein's domain responsible for specific binding to HER2. The nanorod-DARPin (DARPin-GNR) conjugate is specifically bound (in nanomolar concentrations) to human breast adenocarcinoma SK-BR-3 cells overexpressing HER2. Illumination by near-infrared light (850 nm) led to almost complete eradication of the conjugate-treated SK-BR-3 cells; the viability of epithelial human breast cancer cells expressing normal amounts of the receptor was much less affected by the illumination. The results reported here pave the way toward application of DARPin-GNR conjugates in phototherapy of cancer.

2019 - Functionalization of protein hexahistidine tags by functional nanoreactors [Articolo su rivista]
Paolino, M.; Visintin, M.; Margotti, E.; Visentini, M.; Salvini, L.; Reale, A.; Razzano, V.; Giuliani, G.; Caselli, G.; Tavanti, F.; Menziani, Maria Cristina; Cappelli, A.
abstract

A water-soluble Morita-Baylis-Hillman adduct (MBHA) derivative (3) was previously shown to self-assemble in a water environment into functional nanoreactors capable of performing multiple attacks and functionalization of N-acetylhexahistidine. In order to challenge this intriguing reactivity in a model protein more complex than N-acetylhexahistidine, the single-chain Fv antibody CRB0137 was characterized from the point of view of its structure and made to react with 3 in kinetics experiments. The results of these studies suggested that MBHA derivative 3 reacted typically with the amino acid residues of the CRB0137 hexahistidine tag leading to the formation of multi-PEGylated species. Overall, they demonstrate the viability of a new methodology for the site-specific PEGylation of engineered proteins bearing poly-histidine tags.

2019 - H2 Dissociation and Water Evolution on Silver-Decorated CeO2(111): A Hybrid Density Functional Theory Investigation [Articolo su rivista]
Brugnoli, L.; Pedone, A.; Menziani, M. C.; Adamo, C.; Labat, F.
abstract

We present a theoretical investigation of the reactivity of both a pristine CeO2 surface and a small Ag cluster adsorbed on a CeO2 surface toward H2, using a periodic spin-polarized hybrid density functional theory approach. The dissociation of H2 and subsequent formation of H2O have been considered to highlight the role of the metal structure and its underlying metal oxide support as a potential candidate as a catalyst to the above-mentioned reactions. The structural, energetic, electronic, and vibrational properties of all species involved in different reaction paths considered have been fully characterized. The cluster-oxide surface interface has been found to involve the reduction of up to 3Ce4+ to Ce3+, by direct electron transfer from the cluster to the oxide. When comparing the reducibility of the Ag-CeO2 and clean CeO2 systems, O vacancy formation has been found to be hindered along the perimeter of the cluster, while it is promoted underneath the cluster, and is almost unaffected on the surface sites close to the cluster. On the other hand, barriers for the H2 dissociation and the formation of water by H and HO association are lowered with respect to the most favored reaction path found on clean CeO2. These results highlight the key role of metal structures and their underlying oxide support, and especially the three-phase boundary between the gas phase, Ag, and CeO2 as catalysts to such reactions, suggesting potential application as anodic electrocatalysts in fuel cells for example.

2019 - Multiscale Molecular Dynamics Simulation of Multiple Protein Adsorption on Gold Nanoparticles [Articolo su rivista]
Tavanti, F.; Pedone, A.; Menziani, M. C.
abstract

A multiscale molecular dynamics simulation study has been carried out in order to provide in-depth information on the adsorption of hemoglobin, myoglobin, and trypsin over citrate-capped AuNPs of 15 nm diameter. In particular, determinants for single proteins adsorption and simultaneous adsorption of the three types of proteins considered have been studied by Coarse-Grained and Meso-Scale molecular simulations, respectively. The results, discussed in the light of the controversial experimental data reported in the current experimental literature, have provided a detailed description of the (i) recognition process, (ii) number of proteins involved in the early stages of corona formation, (iii) protein competition for AuNP adsorption, (iv) interaction modalities between AuNP and protein binding sites, and (v) protein structural preservation and alteration.

2019 - Nanoreactors for the multi-functionalization of poly-histidine fragments [Articolo su rivista]
Paolino, M.; Reale, A.; Razzano, V.; Giuliani, G.; Donati, A.; Bonechi, C.; Caselli, G.; Visintin, M.; Makovec, F.; Scialabba, C.; Licciardi, M.; Paccagnini, E.; Gentile, M.; Salvini, L.; Tavanti, F.; Menziani, M. C.; Cappelli, A.
abstract

Water-soluble MBHA derivatives were found to self-assemble in a water environment to generate aggregates showing core-shell architectures. The aggregates appeared to be capable of working as nanoreactors performing a multi-functionalization of poly-histidine fragments, which after an initial interaction with the solvated oligo(ethylene glycol) shell reach the reactive core.

2019 - Reducibility of Ag- and Cu-Modified Ultrathin Epitaxial Cerium Oxide Films [Articolo su rivista]
Gasperi, G.; Brugnoli, L.; Pedone, A.; Menziani, M. C.; Valeri, S.; Luches, P.
abstract

The functionality of cerium oxide, and in particular its reactivity, can be significantly altered by the addition of diluted cationic species with different electronic properties as compared to cerium. We investigate the modifications induced by Ag and Cu as modifier cations in cerium oxide ultrathin epitaxial films. The reducibility is assessed by following the modifications of the oxidation state of surface Ce ions by X-ray photoemission spectroscopy, during thermal treatments in ultrahigh vacuum and oxygen partial pressure. A significantly higher reducibility is observed in Ag- and Cu-modified films as compared to pure CeO2 films of the same thickness. The thermal stability of the cation modifier concentration and the changes of the surface structure with the reducing treatments are also discussed. The modifications induced in the material are explained by comparison with density functional theory calculations, which indicate that the oxygen vacancy formation energy is significantly modified by the addition of Ag or Cu in the cerium oxide matrix. The obtained results are of help in view of a rational design of catalysts with optimized performance.

2018 - An atomic-level look at the structure-property relationship of cerium-doped glasses using classical molecular dynamics [Articolo su rivista]
Pedone, Alfonso; Tavanti, Francesco; Malavasi, Gianluca; Menziani, Maria Cristina
abstract

Ce-containing bioactive glasses are of great interest in biomedical field since they exert antioxidant properties associated with low toxicity and a broad spectrum of bacteriostatic activities. The results obtained by classical molecular dynamics simulations allow the elucidation of the correlations between the effect of the inclusion of cerium doping ions into the structure of phosphosilicate and silicate bioactive glasses and their properties. The addition of small quantities of Ce to the silicate bioglass favours the depolymerisation of the silicate network with a positive effect on the ability to dissolve in body fluid. Moreover, the under coordination of both the Ce3+ and Ce4+ species in these glasses enhances their catalytic activity towards hydrogen peroxide. Conversely, the formation of cerium phosphate domains in the phosphosilicate glasses leads to detrimental effects for both the solubility and the catalytic activity of the glasses. Finally, a new quantitative view of the structure-activity relationships governing the macroscopic properties of these glasses has been obtained by means of structural descriptor that takes into account the fragmentation of the Si network and the consequent rearrangement of the modifier ions and the network destruction per cerium unit descriptor.

2018 - Assessment of Density Functional Approximations for Highly Correlated Oxides: The Case of CeO2 and Ce2O3 [Articolo su rivista]
Brugnoli, Luca; Ferrari, Anna Maria; Civalleri, Bartolomeo; Pedone, Alfonso; Menziani, Maria Cristina
abstract

CeO2 based materials are very attractive as catalytic components for industrial processes and environmentally friendly technologies; therefore, a reliable and computationally affordable theoretical description of the main properties of ceria is needed. In particular, the description of the interconversion between the Ce(IV) and Ce(III) oxidation states, on which lies the main chemical features of the cerium oxide, results in quite a challenge at the Density Functional Theory level. Here, we tested several density functional approximations, spanning from GGA to hybrid (Global, Meta-Global, and Range Separated Corrected) functionals, on the structural, vibrational, electronic, and thermochemical properties of bulk CeO2 and Ce2O3. GGA and Meta-GGA xc best predict the thermochemical data, while the discrepancies increase with the introduction of the exact exchange in hybrid functionals. Overall, the Short Range Corrected and Global Hybrid functionals with a percentage of Exact Exchange between 16 and 25 give the best description of the crystal properties. Then, a group of the best performing functionals has been tested on the formation energy of an oxygen vacancy at the (111) CeO2 surface. In general, increasing the amount of exact exchange in the hybrid functionals leads to a better description of the localized Ce 4f states, while the energy of formation of the O vacancy decreases, worsening compared to the experiment.

2018 - Computational Insight into the Effect of Natural Compounds on the Destabilization of Preformed Amyloid-β(1⁻40) Fibrils [Articolo su rivista]
Tavanti, Francesco; Pedone, Alfonso; Menziani, Maria Cristina
abstract

One of the principal hallmarks of Alzheimer's disease (AD) is related to the aggregation of amyloid-β fibrils in an insoluble form in the brain, also known as amyloidosis. Therefore, a prominent therapeutic strategy against AD consists of either blocking the amyloid aggregation and/or destroying the already formed aggregates. Natural products have shown significant therapeutic potential as amyloid inhibitors from in vitro studies as well as in vivo animal tests. In this study, the interaction of five natural biophenols (curcumin, dopamine, (-)-epigallocatechin-3-gallate, quercetin, and rosmarinic acid) with amyloid-β(1⁻40) fibrils has been studied through computational simulations. The results allowed the identification and characterization of the different binding modalities of each compounds and their consequences on fibril dynamics and aggregation. It emerges that the lateral aggregation of the fibrils is strongly influenced by the intercalation of the ligands, which modulates the double-layered structure stability.

2018 - Curcumin derivatives and Aβ-fibrillar aggregates: An interactions’ study for diagnostic/therapeutic purposes in neurodegenerative diseases [Articolo su rivista]
Orteca, Giulia; Tavanti, Francesco; Bednarikova, Zuzana; Gazova, Zuzana; Rigillo, Giovanna; Imbriano, Carol; Basile, Valentina; Asti, Mattia; Rigamonti, Luca; Saladini, Monica; Ferrari, Erika; Menziani, Maria Cristina
abstract

Several neurodegenerative diseases, like Alzheimer's (AD), are characterized by amyloid fibrillar deposition of misfolded proteins, and this feature can be exploited for both diagnosis and therapy design. In this paper, structural modifications of curcumin scaffold were examined in order to improve its bioavailability and stability in physiological conditions, as well as its ability to interfere with β-amyloid fibrils and aggregates. The acid-base behaviour of curcumin derivatives, their pharmacokinetic stability in physiological conditions, and in vitro ability to interfere with Aβ fibrils at different incubation time were investigated. The mechanisms governing these phenomena have been studied at atomic level by means of molecular docking and dynamic simulations. Finally, biological activity of selected curcuminoids has been investigated in vitro to evaluate their safety and efficiency in oxidative stress protection on hippocampal HT-22 mouse cells. Two aromatic rings, π-conjugated structure and H-donor/acceptor substituents on the aromatic rings showed to be the sine qua non structural features to provide interaction and disaggregation activity even at very low incubation time (2h). Computational simulations proved that upon binding the ligands modify the conformational dynamics and/or interact with the amyloidogenic region of the protofibril facilitating disaggregation. Significantly, in vitro results on hippocampal cells pointed out protection against glutamate toxicity and safety when administered at low concentrations (1 μM). On the overall, in view of its higher stability in physiological conditions with respect to curcumin, of his rapid binding to fibrillar aggregates and strong depolymerizing activity, phtalimmide derivative K2F21 appeared a good candidate for both AD diagnostic and therapeutic purposes.

2017 - Computational Insight into the Interaction of Cytochrome C with Wet and PVP-Coated Ag Surfaces [Articolo su rivista]
Tavanti, Francesco; Pedone, Alfonso; Matteini, Paolo; Menziani, Maria Cristina
abstract

In this work, the adsorption of cytochrome C (CytC) on wet 100, 111, 110, and 120 silver surfaces has been investigated by computational simulations. The effect of polyvinylpyrrolidone (PVP) coating has also been studied. The main results obtained can be summarized as follow: (a) CytC strongly interacts with wet bare high index facets, while the adsorption over the 100 surface is disfavored due to the strong water structuring at the surface; (b) a nonselective protein adsorption mechanism is highlighted; (c) the native structure of CytC is well preserved during adsorption; (d) the heme group of CytC is never found to interact directly with the surface; (e) the interactions with the PVP-capped 100 surface is weak and specific. These results can be exploited to better control biological responses at engineered nanosurface, allowing the development of improved diagnostic tools.

2017 - Site-Selective Surface-Enhanced Raman Detection of Proteins [Articolo su rivista]
Matteini, Paolo; Cottat, Maximilien; Tavanti, Francesco; Panfilova, Elizaveta; Scuderi, Mario; Nicotra, Giuseppe; Menziani, Maria Cristina; Khlebtsov, Nikolai; de Angelis, Marella; Pini, Roberto
abstract

Strategies for protein detection via surface enhanced Raman spectroscopy (SERS) currently exploit the formation of randomly generated hot spots at the interfaces of metal colloidal nanoparticles, which are clustered together by intrusive chemical or physical processes in the presence of the target biomolecule. We propose a different approach based on selective and quantitative gathering of protein molecules at regular hot spots generated on the corners of individual silver nanocubes in aqueous medium at physiological pH. Here, the protein, while keeping its native configuration, experiences an intense local E-field, which boosts SERS efficiency and detection sensitivity. Uncontrolled signal fluctuations caused by variable molecular adsorption to different particle areas or inside clustered nanoparticles are circumvented. Advanced electron microscopy analyses and computational simulations outline a strategy relying on a site-selective mechanism with superior Raman signal enhancement, which offers the perspective of highly controlled and reproducible routine SERS detection of proteins.

2017 - Structure of active cerium sites within bioactive glasses [Articolo su rivista]
Benedetti, Francesco; Luches, Paola; D'Addato, Sergio; Valeri, Sergio; Nicolini, Valentina; Pedone, Alfonso; Menziani, Maria Cristina; Malavasi, Gianluca
abstract

The inclusion of small amounts of cerium within the matrix of bioactive glasses, a class of materials used for bone tissue reparation and regeneration, adds a very important antioxidant property. In this work we investigate the local structure around cerium ions in cerium oxide doped bioactive phosphosilicate and silicate glasses, by X-ray absorption fine structure at the Ce K-edge, combined with classical molecular dynamics (MD) simulations. The local structure of the active Ce sites results significantly different from the one in bulk cerium oxide phases. A contracted CeâO first shell distance with respect to bulk oxides is detected, in full agreement with the results of MD simulations. The cerium environment in the glass matrix at different stages of the reaction with H2O2 does not show significant modifications, in spite of the very high catalytic activity. The accurate description of the active Ce sites within bioactive glasses reported in this work is an important step toward an atomic scale understanding of the material functionalities.

2017 - Synthesis, Characterization, and Selective Delivery of DARPin-Gold Nanoparticle Conjugates to Cancer Cells [Articolo su rivista]
Deyev, Sergey; Proshkina, Galina; Ryabova, Anastasiya; Tavanti, Francesco; Menziani, Maria Cristina; Eidelshtein, Gennady; Avishai, Gavriel; Kotlyar, Alexander
abstract

We demonstrate that the designed ankyrin repeat protein (DARPin)_9-29, which specifically targets human epidermal growth factor receptor 2 (HER 2), binds tightly to gold nanoparticles (GNPs). Binding of the protein strongly increases the colloidal stability of the particles. The results of experimental analysis and molecular dynamics simulations show that approximately 35 DARPin_9-29 molecules are bound to the surface of a 5 nm GNP and that the binding does not involve the receptor-binding domain of the protein. The confocal fluorescent microscopy studies show that the DARPin-coated GNP conjugate specifically interacts with the surface of human cancer cells overexpressing epidermal growth factor receptor 2 (HER2) and enters the cells by endocytosis. The high stability under physiological conditions and high affinity to the receptors overexpressed by cancer cells make conjugates of plasmonic gold nanostructures with DARPin molecules promising candidates for cancer therapy.

2017 - Understanding Aggregation-Induced Emission in Molecular Crystals: Insights from Theory [Articolo su rivista]
Presti, Davide; Wilbraham, Liam; Targa, Cecilia; Labat, Frédéric; Pedone, Alfonso; Menziani, Maria Cristina; Ciofini, Ilaria; Adamo, Carlo
abstract

Aggregation-induced emission can often be explained via the restriction of intramolecular rotation paradigm and/or excimer formation. The enhanced luminescence recently observed for aggregates of fluorenone derivatives are no exception. In this work, however, we use a recently developed excited-state electrostatic embedding technique to demonstrate that enhanced emission in diphenylfluorenone can be rationalized by considering a single-molecule process, in which the field induced by the crystalline environment at the excited state enhances the relative brightness of otherwise poorly emissive states, resulting in both enhanced fluorescence and a substantial bathochromic shift in comparison with emission in dilute solution.

2016 - Assessment of the basis set effect on the structural and electronic properties of organic-protected gold nanoclusters [Articolo su rivista]
MUNIZ MIRANDA, Francesco; Menziani, Maria Cristina; Pedone, Alfonso
abstract

We have investigated the structural and optical properties of five monolayer-protected gold nanoclusters with a combination of exchange–correlation functionals, namely B-PBE for the geometry relaxation and CAM-B3LYP for the time-dependent calculations. We have tested the accuracy of five different basis sets in reproducing the experimental structures of these nanoclusters, and we have found that even a rather small basis set (single zeta) can outperform a significantly larger one (double zeta) if some selected atoms are treated with polarization functions. Namely, the sulfur and phosphorous atoms of the capping thiols and phosphines usually are hypervalent when bonded to the gold inner core; therefore, polarization functions allow them significantly more structural flexibility. With the two best performing basis sets, we carried out optical calculations and found that the resulting UV–Vis profiles are largely similar, in particular the energy and orbital contributions of the optical gaps are very close. The results support the use of the small basis set proposed here to investigate larger nanoclusters with general hybrid and range-corrected hybrid functionals.

2016 - Electronic and optical properties of the Au22[1,8-bis(diphenylphosphino) octane]6 nanoclusters disclosed by DFT and TD-DFT calculations [Articolo su rivista]
MUNIZ MIRANDA, Francesco; Presti, Davide; Menziani, Maria Cristina; Pedone, Alfonso
abstract

Time-dependent density functional theory calculations have been used to investigate the electronic and optical properties of a nanocluster composed of two directly bonded Au11 subunits, held together by six bidentate diphosphine ligands: 1,8-bis(diphenylphosphino) octane. Three exchange–correlation functionals have been adopted, a general hybrid (PBE0) and two range-separated hybrids (ωB97X and CAM-B3LYP). The results obtained show that the aforementioned properties are significantly different from those of a previously studied Au11-based nanocluster formed by just one single subunit. In particular, charge transfer excitations from the inner metal core to the outer ligands affect most of the UV–visible spectrum and occur for both alkyl and aromatic ligands. This is particularly evident when thiazole molecules are bonded to the gold core: In this case Au → ligand transitions affect also the first HOMO → LUMO excitation. Moreover, the gold core of this Au22 nanocluster has eight under-coordinated Au surface atoms not engaged in bonds with the ligands. No other known organic-protected gold nanocluster has a similar feature. These gold atoms can be considered as potential in situ active sites for catalysis, their catalytic efficiency and selectivity being modulated by charge distribution.

2016 - Modeling emission features of salicylidene aniline molecular crystals: A QM/QM' approach [Articolo su rivista]
Presti, Davide; Labat, Frédéric; Pedone, Alfonso; Frisch, Michael J.; Hratchian, Hrant P.; Ciofini, Ilaria; Menziani, Maria Cristina; Adamo, Carlo
abstract

A new computational protocol relying on the use of electrostatic embedding, derived from QM/QM' ONIOM calculations, to simulate the effect of the crystalline environment on the emission spectra of molecular crystals is here applied to the beta-form of salicylidene aniline (SA). The first singlet excited states (S-1) of the SA cis-keto and trans-keto conformers, surrounded by a cluster of other molecules representing the crystalline structure, were optimized by using a QM/QM' ONIOM approach with and without electronic embedding. The model system consisting of the central salicylidene aniline molecule was treated at the DFT level by using either the B3LYP, PBE0, or the CAM-B3LYP functional, whereas the real system was treated at the HF level. The CAM-B3LYP/HF level of theory provides emission energies in good agreement with experiment with differences of 220/232 nm (cis-keto form) and 28/214 nm (trans-keto form), respectively, whereas notably larger differences are obtained using global hybrids. Though such differences on the optical properties arise from the density functional choice, the contribution of the electronic embedding is rather independent of the functional used. This plays in favor of a more general applicability of the present protocol to other crystalline molecular systems.

2016 - Optical properties of the dibenzothiazolylphenol molecular crystals through ONIOM calculations: the effect of the electrostatic embedding scheme [Articolo su rivista]
Presti, Davide; Pedone, Alfonso; Ciofini, Ilaria; Labat, Frédéric; Menziani, Maria Cristina; Adamo, Carlo
abstract

Periodic density functional theory (DFT) and hybrid ONIOM time-dependent DFT/MM cluster calculations have been carried out to investigate the ground- and excited-state properties of the crystalline structures of the enolic and ketonic tautomeric forms of a propoxy-substituted dibenzothiazolylphenol molecule (OPr), a prototype for systems undergoing the excited-state intramolecular proton transfer process. The crystalline structures of the tautomeric forms are well reproduced and, as expected, at the ground state, the enol polymorph is predicted to be more stable than the keto one. At the excited state, the effect of the environment on time-dependent DFT calculations has been accounted for by including a charge embedding scheme, and the influence of different kinds of point charges (Mulliken, CM5, RESP and QEq) in determining the optical properties of the central molecule has been investigated. The results reveal that, in fair agreement with experimental data, the absorption (emission) energies of the enol (keto) OPr molecule is red-shifted of about 3 (3) nm going from the gas phase to chloroform and blue-shifted of 10 (23) nm going from the gas to the crystal phase when the electronic embedding with Mulliken charges is employed. The electrostatic embedding influences the excited-state properties more severely than the ground-state properties, and apart the QEq charges, all other models provide Stokes shifts in reasonable agreement with experimental data.

2016 - Phenylindenone isomers as divergent modulators of p38α MAP kinase [Articolo su rivista]
Cappelli, Andrea; Nannicini, Chiara; Chelini, Alessia; Paolino, Marco; Giuliani, Germano; Anzini, Maurizio; Giordani, Antonio; Sabatini, Chiara; Caselli, Gianfranco; Mennuni, Laura; Makovec, Francesco; Giorgi, Gianluca; Vomero, Salvatore; Menziani, Maria Cristina
abstract

Two new fluorophenylindenone derivatives were designed as potential p38α MAPK modulators by preserving the key interactions of the vicinal pyridine/fluorophenyl pharmacophore with the enzyme protein. Interestingly, these two fluorophenylindenone isomers showed divergent activities, with compound 6 behaving as an inhibitor and 5 as a putative activator. These results were rationalized by docking studies and molecular dynamics simulations in terms of stabilization of DFG loop, by compound 5 in a conformation more accessible to phosphorylation.

2016 - The antioxidant properties of Ce-containing bioactive glass nanoparticles explained by Molecular Dynamics simulations [Articolo su rivista]
Pedone, Alfonso; MUNIZ MIRANDA, Francesco; Menziani, Maria Cristina; Tilocca, Antonio
abstract

Molecular dynamics simulations of two glass nanoparticles with composition 25Na2O·25CaO 50SiO2 mol% (Ce-K NP) and 46.1SiO2·24.4Na2O·26.9CaO· 2.6P2O5 mol.% (Ce-BG NP) doped with 3.6 mol% of CeO2 have been carried out in order to explain the enhanced antioxidant properties of the former glass with respect to the latter. The present models show that the different catalase mimetic activity of the two NPs is related to the Ce3+/Ce4+ ratio exposed at their surface. In fact, this ratio is about 3.5 and 13 in the bulk and at the surface of the Ce-BG NP, and 1.0 and 2.1 in the bulk and at the surface of the Ce-K NPs, respectively. Since both oxidation states are necessary for the catalysis of the dismutation reaction of hydrogen peroxides, NPs with a very high Ce3+/Ce4+ ratio possess poorer antioxidant properties. Moreover, our simulations reveal that the already low silicate connectivity found in the bulk glasses examined here is further reduced on the nanoparticle surface, whereas the Na+/Ca2+ ratio rapidly increases. Sodium, calcium and cerium sites in proximity of the surface are found to be under-coordinated, prone to quickly react with water present in physiological environments, thus accelerating the glass biodegradation

2016 - The effect of composition on structural, thermal, redox and bioactive properties of Ce-containing glasses [Articolo su rivista]
Nicolini, Valentina; Varini, Elena; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; Lusvardi, Gigliola; Pedone, Alfonso; Benedetti, Francesco; Luches, Paola
abstract

The effect of phosphate on the ability of Ce-containing bioactive glasses to inhibit oxidative stress was studied on compositions based on Hench (46.2%SiO224.3%Na2O26.9ÊO2.6P2O5, mol%) and Kokubo (50.0%SiO225.0%Na2O25.0ÊO) glasses. In particular, the reduction of catalase mimetic activity of Ce-containing glasses due to the presence: i) of P2O5 in the glass compositions, and ii) of phosphate groups in the solution employed for catalase mimetic activity tests was explained and rationalized by combining SEM, XPS, XRD, DTA, FT-IR and UV-vis experiments with Molecular Dynamics simulations.The results suggest that the Ce ions play a different structural role in the two series of glasses. In particular, in phosphate free glasses Ce is coordinated by non-bridging oxygens (NBOs) originated from the disruption of the silicate network, whereas in phosphate containing glasses the NBOs around Ce ions belong to orthophosphate groups. The latter groups stabilize the Ce3+ species subtracting them from the interconversion process between Ce3+ and Ce4+, which is of fundamental importance for the exhibition of the catalase mimetic activity.

2016 - What can we learn from atomistic simulations of bioactive glasses? [Capitolo/Saggio]
Pedone, A.; Menziani, M. C.
abstract

In the last decades, most experimental efforts have been devoted to design bioactive glasses (please consult the Editor’s note in order to clarify the usage of the terms bioglass, bioactive glass and biocompatible glasses) with enhanced biological and mechanical properties by adding specific ions to known bioactive compositions. Concurrently, computational research has been focused to the understanding of the relationships between bioactivity and composition by rationalization of the role of the doping ions. Thus, a deep knowledge of the structural organization of the constituent atoms of the bioactive glasses has been gained by the employment of ab initio and classical molecular dynamics simulations techniques. This chapter reviews the recent successes in this field by presenting, in a concise way, the structure–properties relationships of silicate, phospho-silicate and phosphate glasses with potential bioactive properties.

2015 - A closer look into the ubiquitin corona on gold nanoparticles by computational studies [Articolo su rivista]
Tavanti, Francesco; Pedone, Alfonso; Menziani, Maria Cristina
abstract

In this study, coarse-grained computational simulations of the ubiquitin corona around gold nanoparticles have been carried out, and the effect of the nanoparticle size (10, 16, 20, and 24 nm diameter) and environment (bare nanoparticle surface, and citrate-coated surface, where citrate are treated with implicit and explicit models) has been analysed. The results showed that the corona is obtained after a slow reorientation step that occurs at the nanoparticle surface in order to optimize the nanoparticle–ubiquitins interaction. The ubiquitin binding modalities depend on the nanoparticle environment, while conformational changes of ubiquitins upon binding and their aggregation propensity slightly depend on nanoparticle size.

2015 - Calcium environment in silicate and aluminosilicate glasses probed by (43)Ca MQMAS NMR experiments and MD-GIPAW calculations [Articolo su rivista]
Gambuzzi, Elisa; Pedone, Alfonso; Menziani, Maria Cristina; Angeli, Frédéric; Florian, Pierre; Charpentier, Thibault
abstract

(43)Ca MQMAS NMR spectra of three silica-based glasses in which Ca(2+) ions play different structural roles have been collected and processed in order to extract the underlying NMR parameter distributions. The NMR parameters have been interpreted with the help of molecular dynamics simulations and DFT-GIPAW calculations. This synergetic experimental-computational approach has allowed us to investigate the Ca environment, to estimate Ca coordination numbers from MD-derived models, and to push further the discussion about (43)Ca NMR sensitivity to the first and second coordination spheres: (43)Ca δiso and Ca-O distance can be successfully correlated as a function of Ca coordination number.

2015 - Competitive Binding of Proteins to Gold Nanoparticles Disclosed by Molecular Dynamics Simulations [Articolo su rivista]
Tavanti, Francesco; Pedone, Alfonso; Menziani, Maria Cristina
abstract

Abstract This work reports the results of coarse-grained molecular dynamics simulations of citrate-coated gold nanoparticles (AuNPs) in interaction with insulin and fibrinogen, two of the most abundant proteins in the plasma. The following have been found: (a) The corona of citrate-coated AuNP of 5 nm core diameter is composed by a single layer of proteins comprising a maximum of 20 insulins, whereas only 3 fibrinogens are contemporaneously present. (b) The binding site for insulin is specific and independent from the number of insulins considered in the computational simulations, whereas fibrinogen presents different binding modes, as a function of protein concentration and composition. Moreover, fibrinogen is able to accommodate two citrate-coated AuNPs in independent binding sites localized at the ending nodes. (c) A competitve process for AuNP binding is observed when insulins and fibrinogens are contemporaneously present in the simulations. (d) The overall protein secondary structure is maintained upon binding to a single citrate-coated AuNP, but small changes in helix and sheet percentages are observed for both proteins. (e) A partial unfolding of the α-helix bundle is found for fibrinogen bound to two AuNPs. This may provide a molecular level understanding of the inflammatory response to nanoparticles. © 2015 American Chemical Society.

2015 - Computational Modeling of Silicate Glasses: A Quantitative Structure-Property Relationship Perspective [Capitolo/Saggio]
Pedone, Alfonso; Menziani, Maria Cristina
abstract

This article reviews the present state of Quantitative Structure-Property Relationships (QSPR) in glass design and gives an outlook into future developments. First an overview is given of the statistical methodology, with particular emphasis to the integration of QSPR with molecular dynamics simulations to derive informative structural descriptors. Then, the potentiality of this approach as a tool for interpretative and predictive purposes is highlighted by a number of recent inspiring applications.

2015 - DFT and TD-DFT assessment of the structural and optoelectronic properties of an organic-Ag14 nanocluster [Articolo su rivista]
Muniz-Miranda, F.; Menziani, M. C.; Pedone, A.
abstract

An extensive benchmark of exchange-correlation functionals on the structure of the X-ray resolved phosphine and thiolate-protected Ag14-based nanocluster, named XMC1, is reported. Calculations were performed both on simplified model systems, with the complexity of the ligands greatly reduced, and on the complete XMC1 particle. Most of the density functionals that yielded good relaxed structures on analogous calculations on gold nanoclusters (viz. those employing the generalized gradient approximation) significantly deform the structure of XMC1. On the contrary, some of the exchange-correlation functionals including part of the exact Hartree-Fock exchange (hybrid functionals) reproduce the experimental geometry with minimal errors. In particular, the widely adopted B3LYP yields fairly accurate structures for XMC1, whereas it is outperformed by many other functionals (both hybrids and generalized gradient corrected) in similar calculations on analogous gold-based systems. Time-dependent density functional calculations have been employed to recover the experimental UV-vis spectrum. The present investigation shows that to correctly reproduce the optical feature of XMC1 the ligands cannot be omitted, because they interact with the metal core at energies much closer to the optical gap than in the case of gold-based nanoclusters of similar sizes. Due to this fact, a functional that accurately describes charge-transfer electronic transitions (such as the long-range corrected CAM-B3LYP) has to be adopted.

2015 - Dynamics of Fracture in Silica and Soda-Silicate Glasses: From Bulk Materials to Nanowires [Articolo su rivista]
Pedone, Alfonso; Menziani, Maria Cristina; Cormack, Alastair N.
abstract

Classical molecular dynamics simulations are used to investigate the fracture mechanism, intrinsic strength, strain at failure and elastic modulus of silica and soda-silicate bulk glasses and nanowires. The latter have been generated by using a new casting approach described in this paper for the first time. The results show that large systems have to be used to reproduce the brittle fracture mechanism of silicate glasses; the appropriate dimensions of the simulation boxes depend on the glass composition. Whereas for silica glass an ideal brittle fracture is observed with models containing 30k atoms, for soda-silicate glasses models with more than 60k atoms should be used. Glasses containing nanovoids and atomic defects (such as under- and overcoordinated silicon and oxygen atoms) are less brittle than flaw-free bulk glasses. The main finding, shown here for the first time, is that the presence of atomic defects and/or modifier cations allows the material to rearrange its structure and absorb the stresses caused by mechanical deformation, the former by transforming from high energy point defects to more stable configurations and the latter by saturating NBOs formed during the gradual breaking of the Si–O bonds that starts soon after the strain at failure is reached. In general, silica nanowires are characterized by lower mechanical properties with respect to bulk models because of the slightly higher amount of atomic defects (3-fold Si, nonbridging oxygens, and small rings) on their surfaces compared to that found in bulk glasses. These defects are not present in soda-silicate nanowires whose surfaces are rich in sodium ions that compensate the negative charge of nonbridging oxygens.

2015 - Evidence of catalase mimetic activity in ce(3+)/ce(4+) doped bioactive glasses [Articolo su rivista]
Nicolini, Valentina; Gambuzzi, Elisa; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; Lusvardi, Gigliola; Pedone, Alfonso; Benedetti, Francesco; Luches, Paola; D'Addato, Sergio; Valeri, Sergio
abstract

The ability of Ce-containing bioactive glasses to inhibit oxidative stress in terms of reduction of hydrogen peroxide, by mimicking the catalase enzyme activity is demonstrated here for the first time. The antioxidant properties of three bioactive glasses containing an increasing amount of CeO2 have been evaluated by following the degradation of hydrogen peroxide with time after immersion in H2O2 aqueous solutions with different concentration. XPS and UV-vis measurements allowed us to determine the Ce(3+)/Ce(4+) ratio in the bulk and on the glass surface, and to correlate it with the ability of the samples to show catalase mimetic activity. Interestingly, we have found that the bioactive glass with composition 23.2Na2O-25.7CaO-43.4SiO2-2.4P2O5-5.3CeO2 immersed in 0.1 M H2O2 aqueous solution is able to degrade 90% of it in 1 week. The reduction in bioactivity of the glasses with increasing CeO2 content is here rationalized in terms of a lower amount of phosphate groups available for the hydroxyapatite layer formation, after binding with cerium ions. In fact, classical molecular dynamics simulations revealed that the addition of CeO2 leads to the formation of cerium phosphate rich regions. The formation of an insoluble CePO4 crystalline phase is also observed by XRD analysis after thermal treatment of the glass samples.

2015 - Influence of Silver Doping on the Photoluminescence of Protected AgnAu25–n Nanoclusters: A Time-Dependent Density Functional Theory Investigation [Articolo su rivista]
Muniz Miranda, Francesco; Menziani, Maria Cristina; Pedone, Alfonso
abstract

The effect of silver doping on the electronic properties and photoluminescence of a class of structurally similar AgnAu25–n2+ nanoclusters (0 ≤ n ≤ 13) has been investigated here by means of time-dependent density functional calculations. As very recently reported in the literature, a mixture of these clusters showed an unexpected 200-fold fluorescence quantum yield boost with respect to Au252+, but no mechanism has been proposed to date to explain this phenomenon. The results presented here suggest that the origin of this boost lies in the nature of the first excited state (S1), which is affected differently by the increasing presence of Ag atoms into the network of Au atoms. In fact, doping the cluster with silver atoms has the effect of shifting the lowest-energy “dark” excited states to higher energy, leaving a very “bright” highest occupied molecular orbital → lowest unoccupied molecular orbital (HOMO → LUMO) transition as the lowest-energy excitation. We propose that when fluorescence occurs from “bright” S1 states, it receives a boost in the quantum yield because of the high oscillator strength of these HOMO → LUMO transitions.

2014 - Arylsulfonyl Groups: The Best Cyclization Auxiliaries for the Preparation of ATRC γ-Lactams can be Acidolytically Removed [Articolo su rivista]
Clark, A. J.; Cornia, Andrea; Felluga, F.; Gennaro, A.; Ghelfi, Franco; Isse, A. A.; Menziani, Maria Cristina; Muniz Miranda, F.; Roncaglia, Fabrizio; Spinelli, D.
abstract

The N-arylsulfonyl group, which is the best and most useful cyclization auxiliary for the transition-metal-catalyzed atom transfer radical cyclization (ATRC) of N-allyl-α-polychloroamides, can be effectively removed from the target γ-lactams by using H2SO4–HOAc, without impairing the halogen functions. The reaction involves H+ attack on the aromatic moiety, and is strongly responsive to the electronic properties of the substituent bound to the aromatic ring: electron-donating groups, such as methyl or methoxy are, in fact, required for efficient “deprotection”. The N-p-nitrophenylsulfonyl cyclization auxiliary, in contrast to all the other sulfonyl groups tested, proved to be unsuitable for the ATRC, owing to a side reductive transposition that halts the redox cycle.

2014 - Assessment of Exchange-Correlation Functionals in Reproducing the Structure and Optical Gap of Organic-Protected Gold Nanoclusters [Articolo su rivista]
Francesco Muniz, Miranda; Menziani, Maria Cristina; Pedone, Alfonso
abstract

Extensive benchmarks of exchange-correlation functionals on real X-ray resolved nanoclusters have been carried out and reported here for the first time. The systems investigated and used for the tests are two undecagold and one Au24+-based nanoclusters stabilized by thiol and phosphine ligands. Time-dependent density-functional theory has been used to compare calculations with experimental data on optical gaps. It has been observed that GGA functionals employing PBE-like correlation (viz., PBE itself, B-PBE, B-P86, and B-PW91) coupled with an improved version of the LANL2DZ pseudopotential and basis set provide accurate results for both the structure and optical gap of gold nanoclusters, at a reasonable computational cost. Good geometries have been also obtained using some global hybrid (e.g., PBE0, B3-P86, mPW1-PW91) and range-separated hybrid (e.g., HSE06) functionals making use of PBE-like correlation, even though they yield optical gaps overestimating the experimental findings up to 0.5 eV. Popular exchange-correlation combinations such as B-LYP and B3-LYP deform cluster geometry during structural optimization, probably due to the LYP correlation. Effects of the stabilizing organic ligands on the properties of metal cores have been probed simulating the nanoclusters at the density-functional level of theory retaining the organic coating. This paper provides a useful contribution to the simulations of structural and optoelectronic properties of larger metal–organic particles suitable for a wide range of nanotechnological applications.

2014 - Computational Protocol for Modeling Thermochromic Molecular Crystals: Salicylidene Aniline As a Case Study [Articolo su rivista]
Presti, Davide; Fréderic, Labat; Pedone, Alfonso; Michael J., Frisch; Hrant P., Hratchian; Ilaria, Ciofini; Menziani, Maria Cristina; Carlo, Adamo
abstract

A computational protocol that combines periodic and QM/QM′ calculations has been applied to investigate the structural (geometrical and electronic) and photophysical absorption properties of the salicylidene aniline (SA) thermochromic molecular crystal. The protocol consists of three different steps, namely (i) the description of the molecular crystal using a periodic approach taking into account dispersion interactions, (ii) the identification of reliable finite models (clusters), and (iii) the calculation of vertical transition energies including environmental effects through the use of an electronic embedding model (QM/QM′ ONIOM approach). The encouraging results obtained in this work for the β polymorph of SA, both in terms of accuracy and computational cost, open the way to the simulation and the prediction of the photophysical behavior of other molecular crystals, especially those much less well characterized experimentally.

2014 - Computational interpretation of 23Na MQMAS NMR Spectra: a comprehensive investigation of the Na environment in silicate glasses [Articolo su rivista]
Gambuzzi, Elisa; Thibault, Chapentier; Menziani, Maria Cristina; Pedone, Alfonso
abstract

Molecular Dynamics, Density Functional Theory calculations and 23Na NMR experiments have been used to inspect the chemical and structural characteristics of the Na environment in soda-lime silicate (CSN) and aluminosilicate (CASN) glasses. The use of an improved 3QMAS pulse sequence has allowed a clear identification of different Na sites. Average coordination numbers have been extracted by fitting the 23Na 3QMAS spectra with the computed NMR parameters. The results show that the 23Na δiso values correlate with the average <Na-O> distances only when the different coordination numbers are explicitly taken into account.

2014 - Dendrimeric tetravalent ligands for the serotonin-gated ion channel [Articolo su rivista]
Marco, Paolino; Laura, Mennuni; Germano, Giuliani; Maurizio, Anzini; Marco, Lanza; Gianfranco, Caselli; Chiara, Galimberti; Menziani, Maria Cristina; Alessandro, Donati; Andrea, Cappelli
abstract

Multivalency is widely used in nature in specific recognition processes. This paper describes an approach to multivalency in the pentameric 5-HT 3 receptor, a ligand-gated ion channel, which constitutes an example of intrinsically multivalent biological receptors. Owing to the picomolar K i value, TETRA-L represents an outstanding multivalent ligand for the neurotransmitter receptor.

2014 - On the opto-electronic properties of phosphine and thiolate-protected undecagold nanoclusters [Articolo su rivista]
Francesco Muniz, Miranda; Menziani, Maria Cristina; Pedone, Alfonso
abstract

We present here a detailed time-dependent density-functional theory investigation aimed at systematically dissecting the electronic spectra of two thiolate and phosphine protected undecagold nanoclusters. Calculations performed on the experimental structures of Au11(PPh3)7Cl3 and Au11(PPh3)7(SPyr)3 show that ligands have negligible contributions in the visible region. Metal → ligand charge transfer transitions appear at energies well above the visible threshold, while transitions with some small ligand → metal and ligand → ligand character occur sporadically at even higher energies. Thus, the conjugation effect between the π-electrons of the ligand and electrons of gold, recently hypothesized to interpret the spectra of phosphine and thiolate-protected nanoclusters, is not confirmed by the results of this study.

2014 - Oxalyl Dihydrazide Polymorphism: a Periodic Dispersion-Corrected DFT and MP2 Investigation. [Articolo su rivista]
Presti, Davide; Pedone, Alfonso; Menziani, Maria Cristina; B., Civalleri; Lorenzo, Maschio
abstract

The molecular crystal of oxalyl dihydrazide differentiates into five polymorphs that are governed by inter- and intramolecular hydrogen bonds. The complex mixture of such interactions with long range dispersive forces makes its computational characterization very challenging; thus it represents an ideal benchmark for ab initio methods when striving for a description of polymorphism in molecular crystals. Indeed, a complete experimental energetic profile of this system is still lacking, and it is here investigated by means of periodic dispersion-corrected DFT and Local second order Møller–Plesset Perturbation theory (LMP2) calculations. In this work, the empirical dispersion correction schemes proposed by Tkatchenko and Scheffler (TS) [Tkatchenko et al., Phys. Rev. Lett., 2009, 102, 073005] and Grimme (D2) [Grimme, J. Comput. Chem., 2006, 27, 1787] have been used in combination with the PBE semilocal functional for geometry optimizations. We observed that PBE-TS provides a remarkable improvement in predicting the crystal structure of oxalyl dihydrazide polymorphs with respect to commonly used DFT-D functionals. The relative stabilities of the five forms have then been computed at the PBE-TS/D2, PBE0-D2, B3LYP-D2 and B3LYP-D3(BJ)+gCP level on the PBE-TS hydrogen-optimized geometries and benchmarked against high level periodic LMP2 calculations. PBE-TS, B3LYP-D2 and B3LYP-D3(BJ)+E(3) (that is including three-body corrections) achieve good predictions of the stability ordering, though the broadness of the energy range is slightly larger than in the case of LMP2.

2014 - Probing silicon and aluminium chemical environments in silicate and aluminosilicate glasses by solid state NMR spectroscopy and accurate first-principles calculations [Articolo su rivista]
Gambuzzi, Elisa; Pedone, Alfonso; Menziani, Maria Cristina; Frédéric, Angeli; Daniel, Caurant; Thibault, Charpentier
abstract

Silicon and aluminium chemical environments in silicate and aluminosilicate glasses with compositions 60SiO(2)center dot 20Na(2)O center dot 20CaO (CSN), 60SiO(2)center dot 20Al(2)O(3)center dot 20CaO (CAS), 78SiO(2)center dot 11Al(2)O(3)center dot 11Na(2)O (NAS) and 60SiO(2)center dot 10Al(2)O(3)center dot 10Na(2)O center dot 20CaO (CASN) have been investigated by Al-27 and Si-29 solid state magic angle spinning (MAS) and multiple quantum MAS (MQMAS) nuclear magnetic resonance (NMR) experiments. To interpret the NMR data, first-principles calculations using density functional theory were performed on structural models of these glasses. These models were generated by Shell-model molecular dynamics (MD) simulations. The theoretical NMR parameters and spectra were computed using the gauge including projected augmented wave (GIPAW) method and spin-effective Hamiltonians, respectively. This synergetic computational-experimental approach offers a clear structural characterization of these glasses, particularly in terms of network polymerization, chemical disorder (i.e. Si and Al distribution in second coordination sphere) and modifier cation distributions. The relationships between the local structural environments and the Si-29 and Al-27 NMR parameters are highlighted, and show that: (i) the isotropic chemical shift of both Si-29 and Al-27 increases of about +5 ppm for each Al added in the second sphere and (ii) both the Al-27 and Si-29 isotropic chemical shifts linearly decrease with the reduction of the average Si/Al-O-T bond angle. Conversely, Al-27 and Si-29 NMR parameters are much less sensitive to the connectivity with triple bridging oxygen atoms, precluding their indirect detection from Al-27 and Si-29 NMR. (C) 2013 Elsevier Ltd. All rights reserved.

2014 - Synthesis and structureeactivity relationship studies in serotonin 5-HT4 receptor ligands based on a benzo[de][2,6]naphthridine scaffold [Articolo su rivista]
Federica, Castriconi; Marco, Paolino; Germano, Giuliani; Maurizio, Anzini; Giuseppe, Campiani; Laura, Mennuni; Chiara, Sabatini; Marco, Lanza; Gianfranco, Caselli; DE RIENZO, Francesca; Menziani, Maria Cristina; Maria, Sbraccia; Paola, Molinari; Tommaso, Costa; Andrea, Cappelli
abstract

A small series of serotonin 5-HT4 receptor ligands has been designed from flexible 2-methoxyquinoline compounds 7a,b by applying the conformational constraint approach. Ligands 7a,b and the corresponding conformationally constrained analogues 8aeg were synthesized and their interactions with the 5-HT4 receptor were examined by measuring both binding affinity and the ability to promote or inhibit receptoreG protein coupling. Ester derivative 7a and conformationally constrained compound 8b were demonstrated to be the most interesting compounds showing a nanomolar 5-HT4R affinity similar to that shown by reference ligands cisapride (1) and RS-23,597-190 (4). The result was rationalized by docking studies in term of high similarity in the binding modalities of flexible 7a and conformationally constrained 8b. The intrinsic efficacy of some selected ligands was determined by evaluating the receptoreG protein coupling and the results obtained demonstrated that the nature and the position of substituents play a critical role in the interaction of these ligands with their receptor.

2014 - Unraveling the Polymorphism of [(p-cymene)Ru(κN-INA)Cl2] through Dispersion-Corrected DFT and NMR GIPAW Calculations [Articolo su rivista]
Presti, Davide; Pedone, Alfonso; Menziani, Maria Cristina
abstract

The structural and 13C/1H NMR parameters of the four crystal forms (1α, 1·H2O, 1β, and 1γ) of the solid wheel-and-axle (WAA) metal–organic compound [(p-cymene)Ru(κN-INA)Cl2] have been studied by means of periodic DFT calculations. The quality of the results obtained strongly depends on a correct description of long-range interactions; thus, in the geometry refinement protocol used, the pure DFT functionals need to be coupled with a dispersion-correction term (B3LYP-D2, B3LYP-D*). The solid-state 13C/1H NMR δiso parameters and 13C MAS NMR spectra, calculated by means of the PBE-GIPAW method, agree well with the experimental data for the four crystal forms (mean absolute deviations of the 13C and 1H δiso data values lie in the ranges 1.3–2.9 and 0.3–1.0 ppm, respectively). In this context, some revisions in the experimental assignment of the 13C/1H NMR δiso parameters of the 1·H2O, 1β, and 1γ crystal forms can be suggested. The mismatch in the assignment seems to be due to the rotation of the −COOH moiety, which occurs at the 1α–1·H2O transition and was not considered in the experiments. Finally, the results obtained suggest the presence of two COOH···Cl hydrogen bonds of comparable strength established by the two molecules in the asymmetric unit of the 1γ polymorph, in partial disagreement with previous findings.

2013 - Approaching the 5-HT3 receptor heterogeneity by computational studies of the transmembrane and intracellular domains [Articolo su rivista]
Marta Del, Cadia; DE RIENZO, Francesca; Menziani, Maria Cristina
abstract

5-hydroxytryptamine type-3 receptor (5-HT3), an important target of many neuroactive drugs, is a cation selective transmembrane pentamer whose functional stoichiometries and subunit arrangements are still debated, due to the extreme complexity of the system. The three dimensional structure of the 5-HT3R subunits has not been solved so far. Moreover, most of the available structural and functional data is related to the extracellular ligand-binding domain, whereas the transmembrane and the intracellular receptor domains are far less characterised, although they are crucial for receptor function. Here, for the first time, 3D homology models of the transmembrane and the intracellular receptor domains of all the known human 5-HT3 subunits have been built and assembled into homopentameric (5-HT3AR, 5-HT3BR, 5-HT3CR, 5-HT3DR and 5-HT3ER) and heteropentameric receptors (5-HT3AB, 5-HT3AC, 5-HT3AD and 5-HT3AE), on the basis of the known three-dimensional structures of the nicotinic-acetylcholine receptor and of the ligand gated channel from Erwinia chrysanthemi. The comparative analyses of sequences, modelled structures, and computed electrostatic properties of the single subunits and of the assembled pentamers shed new light both on the stoichiometric composition and on the physicochemical requirements of the functional receptors. In particular, it emerges that a favourable environment for the crossing of the pore at the transmembrane and intracellular C terminus domain levels by Ca2+ ions is granted by the maximum presence of two B subunits in the 5-HT3 pentamer.

2013 - Bioglasses: glasses for medical applications [Capitolo/Saggio]
Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; Pedone, Alfonso
abstract

bioglasses for medical applications

2013 - Computational simulations of solid state NMR spectra: a new era in structure determination of oxide glasses [Articolo su rivista]
Thibault, Charpentier; Menziani, Maria Cristina; Pedone, Alfonso
abstract

The application of the MD-GIPAW approach to the calculation of NMR parameters, line widths and shapes of the spectra of oxide glasses is reviewed. Emphasis is given to the decisive role of this approach both as an interpretative tool for a deeper understanding of the spectral behavior of complex systems and as a predictive instrument to map NMR data in a distribution of structural parameters and vice versa (structural inversion method). After a brief overview of the basic features of oxide glasses and the experimental techniques routinely employed to investigate their structure, a general description of the computational methods usually adopted to generate sound structural models of amorphous materials is offered. The computational recipe used to compute the solid state NMR spectra of oxide glasses and to establish quantitative structural-NMR property relationships is then described. Finally, these concepts are applied to 'simple' network former glasses and more complex silicates, aluminosilicate, phosphosilicate and borosilicate glasses of scientific relevance. The final section is dedicated to the future developments that will hopefully improve the computational approach described overcoming some of the current limitations.

2013 - Exploring a potential palonosetron allosteric binding site in the 5-HT 3 receptor [Articolo su rivista]
Del Cadia, M; DE RIENZO, Francesca; Weston D., A; Thompson A., J; Menziani, Maria Cristina; Lummis, S. C. R.
abstract

Palonosetron (Aloxi) is a potent second generation 5-HT3 receptor antagonist whose mechanism of action is not yet fully understood. Palonosetron acts at the 5-HT3 receptor binding site but recent computational studies indicated other possible sites of action in the extracellular domain. To test this hypothesis we mutated a series of residues in the 5-HT3A receptor subunit (Tyr73, Phe130, Ser 163, and Asp165) and in the 5-HT3B receptor subunit (His73, Phe130, Glu170, and Tyr143) that were previously predicted by in silico docking studies to interact with palonosetron. Homomeric (5-HT3A) and heteromeric (5-HT3AB) receptors were then expressed in HEK293 cells to determine the potency of palonosetron using both fluorimetric and radioligand methods to test function and ligand binding, respectively. The data show that the substitutions have little or no effect on palonosetron inhibition of 5-HT-evoked responses or binding. In contrast, substitutions in the orthosteric binding site abolish palonosetron binding. Overall, the data support a binding site for palonosetron at the classic orthosteric binding pocket between two 5-HT3A receptor subunits but not at allosteric sites previously identified by in silico modelling and docking.

2013 - Local versus Average Structure in LaSrAl3O7: A NMR and DFT Investigation [Articolo su rivista]
Chiara, Ferrara; Cristina, Tealdi; Pedone, Alfonso; Menziani, Maria Cristina; Aaron J., Rossini; Guido, Pintacuda; Piercarlo, Mustarelli
abstract

LaSrAl3O7 belongs to the family of (M2T(1)T(2)O7)-T-1-O-2 compounds with tetragonal melilite-like layered structure. In such compounds the local structure and properties may be very different from the average ones, mainly due to cationic disorder on the M site. In this work, solid-state Al-27 NMR spectroscopy and periodic density functional theory calculations were used to highlight the differences between local and average order in the LaSrAl3O7 crystal. The Al-27 isotropic chemical shifts and quadrupolar coupling constants were computed by employing the gauge including projector augmented wave (GIPAW) and PAW formalisms, respectively. An impressive linear relationship between the computed quadrupolar coupling constant C-Q and the Al tetrahedra (T-1, T-2) distortion was observed. In particular, our calculations showed that the distortion of the T-2 environment is determined by the La/Sr speciation around the apical nonbridging oxygen.

2013 - New insights into the bioactivity of SiO2–CaO and SiO2–CaO–P2O5 sol–gel glasses by molecular dynamics simulations [Articolo su rivista]
Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; Pedone, Alfonso; A. J., Salinas; M., Vallet Regı
abstract

The structures of binary xCaO . (100 - x)SiO2glasses with x = 10, 20 and 30 mol-% and ternary(20 - x)CaO . xP2O5 . 80SiO2 glasses with x = 3, 10, 15,17 and 20 mol-% have been studied by means of classicalmolecular dynamics simulations using both the melt-quenchedand the sol–gel protocols. The structural picturederived correlates the bioactive behaviour to the combinedeffects of the connectivity of the extended silicate networkand to the tendency to form (or not to form) non-homogeneousdomains. In this context, a mathematical relationshipthat relates the Ca/P ratio in the Ca phosphatemicro-segregation zones to the P2O5 content in ternaryglasses has been developed and this has been used to finetuningthe optimum amount of P in a glass for its highest invitro bioactivity. The composition with optimal Ca/P ratio,80SiO2 . 14.8CaO . 5.2P2O5 has been synthesized and the results of bioactivity tests have confirmed the prediction.

2013 - Novel Route to Chaetomellic Acid A and Analogues: Serendipitous Discovery of a more Competent FTase Inhibitor [Articolo su rivista]
Bellesia, Franco; Seoung ryoung, Choi; Fulvia, Felluga; Giuliano, Fiscaletti; Ghelfi, Franco; Menziani, Maria Cristina; Andrew F., Parsons; C., Dale Poulter; Roncaglia, Fabrizio; Massimo, Sabbatini; Domenico, Spinelli
abstract

A new practical route to chaetomellic acid A (ACA), based on the copper catalysed radical cyclization (RC) of (Z)-3-(2,2-dichloropropanoyl)-2-pentadecylidene-1,3-thiazinane, is described. Remarkably, the process entailed: (i) a one-pot preparation of the intermediate N-a-perchloroacyl-2-(Z)-alkyliden-1,3-thiazinanes starting from N-(3-hydroxypropyl)palmitamide, (ii) a two step smooth transformation of the RC products into ACA and (iii) only one intermediate chromatographic purification step. The method offers a versatile approach to the preparation of ACA analogues, through the synthesis of an intermediate maleic anhydride with a vinylic group at the end of the aliphatic tail, a function that can be transformed through a thiol–ene coupling. Serendipitously, the disodium salt of 2-(9-(butylthio)nonyl)-3-methylmaleic acid, that we prepared as a representative sulfurated ACA analogue, was a more competent FTase inhibitor than ACA. This behaviour was analysed by a molecular docking study.

2013 - Study of the Structural Role of Gallium and Aluminum in 45S5 Bioactive Glasses by Molecular Dynamics Simulations [Articolo su rivista]
Malavasi, Gianluca; Pedone, Alfonso; Menziani, Maria Cristina
abstract

The structural properties of phosphosilicate glasses based on the 45S5 Bioglass doped with gallium and aluminum (46.2SiO(2)center dot 24.3Na(2)O center dot 26.9CaO center dot 2.6P(2)O(5)center dot 1.0X(2)O(3), X = Ga or Al) are investigated by means of classical molecular dynamics simulations. Structural features of the two compositions are compared with those of the original 45S5 Biog,lass in order to relate them to the different known bioactivities of these materials. Differences in the coordination environments of Ga and Al, network connectivity, and ion aggregation reveal a microscopic model of these glasses which supports the interpretation of the experimental data and provides new insight into the different biological behaviors of Ga- and Al-containing phosphosilicate glasses. Although Ga is found predominantly in a 4-fold coordination environment, small amounts of 5- and 6-fold coordinated atoms have been detected depending on the interatomic potential model employed. This suggests its possible intermediate role in phosphosilicate glasses. On the contrary, Al plays a network former role and leads to glasses with a more polymerized structure. Interestingly, the results show an increased propensity for aggregation of the Ca2+ and PO43- ions in the Al-containing phosphosilicate glasses with respect to the Ga-containing ones. This leads to insoluble calcium-phosphate-rich regions not detected in the bioactive glasses

2012 - A first step towards the understanding of the 5-HT3 receptor subunitheterogeneity from a computational point of view [Articolo su rivista]
DE RIENZO, Francesca; DEL CADIA, Marta; Menziani, Maria Cristina
abstract

The functional serotonin type-3 receptor (5-HT3-R), which is the target of many neuroactive drugs, isknown to be a homopentamer made of five identical subunits A (5-HT3A-R) or a binary heteropentamermade of subunits A and B (5-HT3A/B-R) with a still debated arrangement and stoichiometry. Thiscomplex picture has been recently further complicated by the discovery of additional 5-HT3-R subunits,C, D, and E, which, similarly to the B subunit, are apparently able to form functional receptors only ifco-expressed with subunit A. Being the binding site for both serotonin and antagonists (i.e. drugs)located at the extracellular interface between two adjacent subunits, the large variability of the 5-HT3-Rcomposition becomes a crucial issue, since it can originate many different interfaces providing nonequivalentligand binding sites and complicating the pharmacological modulation. Here, the different5-HT3-R interfaces are analysed, on the bases of the structural conformations of previously built 3Dhomology models and of the known subunit sequences, by addressing their physicochemicalcharacterization. The results confirm the presence of an aromatic cluster located in the core of the A–Ainterface as a key determinant for having an interface both stable and functional. This is used as adiscriminant to make hypotheses about the capability of all the other possible interfaces constituted bythe known 5-HT3-R sequences A, B, C, D, and E to build active receptors.

2012 - Computational Insights into ADAMTS4, ADAMTS5 andMMP13 Inhibitor Selectivity [Articolo su rivista]
FILOMIA, Federico; SAXENA, PUNEET; DURANTE, Caterina; DE RIENZO, Francesca; COCCHI, Marina; MENZIANI, Maria Cristina
abstract

The results obtained by means of Molecular Dynamicssimulations and Multiway Explorative Data Analysison ADAMTS4, ADAMTS5 and MMP13 complexed with Marimastatand two cis-1(S)2(R)-amino-2-indanol ligands suggestthat determinant characteristics for ligand binding andselectivity among the three enzymes are to be found in thedifferent protein conformation flexibility. Moreover, the role of the TS-domain in the inhibitor binding to ADAMTS enzymeshas been investigated for the first time in this work.The results obtained suggest that the influence of the TSdomainon the S1’ loop fluctuations of ADAMTS4 andADAMTS5 could be exploited for the design of therapeuticsfor chronic osteoarthritis diseases.

2012 - First-principles simulations of the 27Al and 17O solid-state NMR spectra of the CaAl2Si3O10 glass [Articolo su rivista]
Pedone, Alfonso; Gambuzzi, Elisa; Malavasi, Gianluca; Menziani, Maria Cristina
abstract

The local and medium-range structure of the 20CaO·20Al2O3·60SiO2 glass generated by classical molecular dynamics simulations has been compared to NMR experiments by computing the 27Al and 17O NMR parameters and NMR spectra from first-principles simulations. The calculation of the NMR parameters (chemical shielding and quadrupolar parameters), which are then used to simulate solid-state MAS and 3QMAS NMR spectra, is achieved by the gauge including projector augmented-wave and the projector augmented-wave methods on the DFT-PBE relaxed structure. The NMR spectra calculated with the present approach are found to be in excellent agreement with the experimental data, providing an unambiguous view of the local and medium-range structure of aluminosilicate glasses.

2012 - Modeling the Binding Affinity of p38a MAPKinase Inhibitors by Partial Least SquaresRegression [Articolo su rivista]
Basant, Nikita; Durante, Caterina; Cocchi, Marina; Menziani, Maria Cristina
abstract

The p38 mitogen-activated protein kinase is activatedby environmental stress and cytokines andplays a role in transcriptional regulation andinflammatory responses. Factors influencing theactivity and selectivity of the p38a mitogen-activatedprotein kinase inhibitors have been investigatedin this paper by inspecting the bindingorientation and the possible residue-inhibitorinteractions in the binding site. The binding patternof a set of 45 different inhibitors against p38amitogen-activated protein kinase was studiedthrough Molecular Dynamic Simulations of theprotein-inhibitor complexes. Further, Partial LeastSquares regression was used to develop a QuantitativeStructure Activity Relationship model topredict the binding affinities of ligands. Theselected model successfully predicted the test setwith a Root Mean Square Error of Prediction of1.36. The regression coefficients and the VariableImportance in Projection plots highlighted the residue-inhibitor interactions which exhibited thelargest absolute effect on the ligand binding, suchas the van der Waals interaction with LYS50,ILE81, ASP165; electrostatic interactions withSER29, LEU164; hydrogen bonds with MET106;and total energy interaction with SER29 andLEU83.

2012 - On the ability of Periodic Dispersion-Corrected DFT Calculations to Predict Molecular Crystal Polymorphism in para-diiodobenzene [Articolo su rivista]
Pedone, Alfonso; Presti, Davide; Menziani, Maria Cristina
abstract

Periodic DFT calculations employing the PBE, PBE0 and B3LYP functionals coupled with different dispersion correction schemes have been applied to para-diiodobenzene molecular crystal in order to determine how they perform in reproducing the energetic and crystal geometry of its two well known polymorphs.Our results demonstrate that, provided that the dispersion correction scheme proposed by Tkatchenko and Scheffler [Phys. Rev. Lett. 102 (2009) 073005] is used, DFT can be successfully employed to predictthe geometric structure and energy ordering of the a and b forms of para-diiodobenzene molecular crystal, with an accuracy comparable to that yielded by diffusion Monte Carlo calculations.

2012 - The extracellular subunit interface of the 5-HT3 Receptors: a Computational Alanine Scanning Mutagenesis study Journal of Biomolecular Structure and Dynamics [Articolo su rivista]
DE RIENZO, Francesca; MOURA BARBOSA, ARMENIO JORGE; M. A. S., Perez; P. A., Fernandes; M. J., Ramos; Menziani, Maria Cristina
abstract

The functional serotonin 5-HT type-3 (5-HT3) receptor, the target of many neuroactive drugs, is known to be apseudo-symmetric pentamer made either of five identical subunits A (homomeric 5-HT3A-R) or of subunits A and B(heteromeric 5-HT3A/B-R) in a still debated arrangement. The serotonin binding site is located in the extracellular region,at the interface between two monomers, called the principal and the complementary subunits. The results of moleculardynamics simulations and computational alanine scanning mutagenesis studies applied here to the homomeric human5-HT3A-R disclose an aromatic “hot” cluster in the centre of the interface formed by residues W178 (principal subunit),Y68, Y83, W85 and Y148 (complementary subunit). Moreover, investigation of the coupling of agonist/antagonist bindingto channel activation/inactivation points out the presence of two putative functional pathways at the subunit interface:W116-H180-L179-W178-E124-F125 (principal subunit) and Y136-Y138-Y148-W85-(P150) (complementary subunit),where W178 and Y148 appear to be critical residues for the binding/activation mechanism. Finally, direct comparison ofthe main features shown by the AA interface in the human 5-HT3A-R with those of the BB interface in the homopentamerichuman 5-HT3B-R provides interesting clues about the possible reasons that cause the 5-HT3B-R not to befunctional.

2012 - The structure of fluoride-containing bioactive glasses: new insights from first-principles calculations and solid state NMR spectroscopy. [Articolo su rivista]
Pedone, Alfonso; T., Charpentier; Menziani, Maria Cristina
abstract

Fluoride-containing bioactive glasses are attracting particular interest in many fields of dentistry and orthopedic because they combine the bone-bonding ability of bioactive glasses with the anticariogenic protection provided by fluoride ions. Since the biomedical applications of these materials critically depend on the release of ionic species in the surrounding physiological environment, a deep knowledge of their environments is required. In this paper, Density Functional Theory calculations and Spin Effective Hamiltonians have been employed to analyse the NMR signatures of the various environments of 19F, 29Si, 31P and 23Na atoms in fluorinated bioglasses structural models previously generated by Car-Parrinello Molecular Dynamics simulations. Comparison with experimental spectra expressly recorded in this work shows a good agreement and allows the enlightenment of some longstanding issues about the atomic structure of fluorinated bioglasses, such as the presence of Si-F and Si-O-P bonds. In particular, it is shown that Si-F bonds cannot be resolved by using MAS NMR experiments only, and 29Si{19F} REDOR experiments, that probes directly spatial proximities among atoms, must be employed. Our results show that F is coordinated entirely to the modifier ions Na and Ca, and that no Si-F bonds are present in the real glass structure. Thus, addition of fluorine to the 45S5 Bioglass® increases the polymerization of the silicate network by removing modifiers from the siliceous matrix and reducing its reactivity. Finally, the computed isotropic chemical shifts of the various environments of phosphorous show that, if present, Si-O-P bonds should be clearly noticeable in the 31P static NMR experimental spectrum. Instead, the latter shows that P is present as isolated orthophosphate units and does not enter into the siliceous matrix by forming Si-O-P bonds as conjectured by Molecular Dynamics simulations.

2012 - Unambiguous Description of the Oxygen Environment in Multicomponent Aluminosilicate Glasses from 17O Solid State NMR Computational Spectroscopy [Articolo su rivista]
Pedone, Alfonso; Gambuzzi, Elisa; Menziani, Maria Cristina
abstract

Classical molecular dynamics simulations, density functional theory calculations, and spin-effective Hamiltonians have been used to simulate the 17O MAS and 3QMAS NMR spectra of Ca−Na silicate and aluminosilicate glasses and melts employed as simplified models for basaltic, andesitic, and rhyolitic magmas. The direct comparison of the theoretical NMR spectra of molecular dynamics derived structural models with the experimental counterparts available in the literature has allowed the investigation of the nature of nonframework cation mixing and the extent of intermixing among framework units in Na−Ca aluminosilicate glasses. In particular, in agreement with previous experimental evidence, the results show a nonrandomdistribution of the network-modifying Ca and Na in soda-lime glasses with the prevalence of dissimilar Na−Ca pairs around nonbridging oxygens. The oxygen sites are not completely resolved in the MAS spectra of the aluminosilicate glasses. On the contrary, in the 17O 3QMAS spectra the multiple oxygen sites, in particular the Si−O−Si,Al−O−Al, Al−O−Si, and the nonbridging oxygen peaks, are distinguishable. The small amount of Al−O−Al sites found in theinvestigated glasses reveals that the Al avoidance rule is not respected in amorphous solids. The Si−O−Al sites are surrounded byNa ions, which play a preferential role as a charge-balancing cation, while Ca can act as a network-modifying cation. Finally, correlations between the structural characteristic and the values of the NMR parameters have been attempted with the aim of helping the interpretation of NMR spectra of glasses with similar compositions.

2011 - Bivalent Ligands for the Serotonin 5-HT3 Receptor [Articolo su rivista]
A., Cappelli; M., Manini; M., Paolino; A., Gallelli; M., Anzini; L., Mennuni; DEL CADIA, Marta; DE RIENZO, Francesca; Menziani, Maria Cristina; S., Vomero
abstract

The serotonin 5-HT3 receptor is a ligand-gated ion channel, which by virtue of its pentameric architecture, canbe considered to be an intriguing example of intrinsicallymultivalent biological receptors. This paper describes a generaldesign approach to the study of multivalency in this multimericion channel. Bivalent ligands for 5-HT3 receptor have beendesigned by linking an arylpiperazine moiety to probes showing different functional features. Both homobivalent and hetero- bivalent ligands have shown 5-HT3 receptor affinity in the nanomolar range, providing evidence for the viability of our design approach. Moreover, the high affinity shown by homo- bivalent ligands suggests that bivalency is a promising approachin 5-HT3 receptor modulation and provides the rational basis for applying the concepts of multivalency to the study of 5-HT3 receptor function.

2011 - Fluorine environment in bioactive glasses: ab initio molecular dynamics simulations. [Articolo su rivista]
J. K., Christie; PEDONE, Alfonso; MENZIANI, Maria Cristina; A., Tilocca
abstract

Car-Parrinello molecular dynamics (CPMD) simulations have been performed on a 45S5Bioglass composition in which 10 mol% of the CaO has been replaced with CaF2. The veryaccurate characterization of the fluorine environment in this system has allowed us to resolvesome longstanding issues about the atomic structure of fluorinated bioglasses. F is coordinatedalmost entirely to the modifier ions Na and Ca, with a very small amount of residual Si-Fbonds, whose fraction only becomes significant in the melt precursor. There is no evidencefor preferential bonding of F to either modifier ion: almost all F atoms are coordinated toboth calcium and sodium in a “mixed state”, rather than exclusively to either, as had beenconjectured. We discuss the consequences of these findings on the properties of fluorinecontainingbioglasses.

2010 - Computational analysis of ligand recognition sites of homo- andheteropentameric 5-HT3 receptors [Articolo su rivista]
Moura Barbosa, Armenio Jorge; De Rienzo, Francesca; M. J., Ramos; Menziani, Maria Cristina
abstract

Inhibition of the 5-hydroxytryptamine receptor (5-HT3R), a member of the Cys-loop superfamily ofLigand-Gated Ion Channels (LGICs), has been recognized to have important antiemetic effects. Withrespect to the many other drugs already in use, such as the first generation 5-HT3R antagonist granisetron,palonosetron, a second generation antagonist, clearly demonstrates superior inhibition potencytowards the 5-HT3Rs. Five different receptor monomers, the 5-HT3R AeE, have been identified althoughthe A and B subunits are the only known to build functional receptors, the homopentameric 5-HT3AR andthe heteropentameric 5-HT3BeAR (with BBABA subunit arrangement). At present, however, no threedimensionalstructure has been reported for any of the 5-HT3R subunits. To understand the bindingproperties of agonists and antagonists, models of the extracellular portion of the 5-HT3R A and B subunitsare built and assembled into the receptor (homo- and hetero-) pentameric structure on the basis of theknown three-dimensional structure of the nicotinic-acetylcholine receptor (nACh-R). The results ofdocking studies of the natural agonist serotonin and the antagonists palonosetron and granisetron intothe modelled homomeric and heteromeric 5-HT3R binding interfaces, provide a possible rationalizationboth of the higher potency of palonosetron with respect to other antagonists, and of its previouslyreported allosteric binding and positive cooperativity properties

2010 - Extension of the AMBER force-field for the study of large nitroxides incondensed phases: an ab initio parameterization [Articolo su rivista]
E., Stendardo; Pedone, Alfonso; P., Cimino; Menziani, Maria Cristina; O., Crescenzi; V., Barone
abstract

The popular AMBER force-field has been extended to provide an accurate description of largeand flexible nitroxide free-radicals in condensed phases. New atom types have been included, andrelevant parameters have been fitted based on geometries, vibrational frequencies and potentialenergy surfaces computed at the DFT level for several different classes of nitroxides, bothin vacuo and in different solvents. The resulting computational tool is capable of providingreliable structures, vibrational frequencies, relative energies and spectroscopic observables forlarge and flexible nitroxide systems, including those typically used as spin labels. The modifiedforce field has been employed in the context of an integrated approach, based on classicalmolecular dynamics and discrete–continuum solvent models, for the investigation ofenvironmental and short-time dynamic effects on the hyperfine and gyromagnetic tensors ofPROXYL, TEMPO and INDCO spin probes. The computed magnetic parameters are in verygood agreement with the available experimental values, and the procedure allows for an unbiasedevaluation of the role of different effects in tuning the overall EPR observables.

2010 - Insight into MAPK P38α DFG-Flip mechanism by accelerated molecular dynamics [Articolo su rivista]
Filomia, Federico; DE RIENZO, Francesca; Menziani, Maria Cristina
abstract

The DFG motif at the beginning of the activation loop of the MAPK p38a undergoes a local structural reorganizationupon binding of allosteric type-II and type-III inhibitors, which causes the residue F169 to movefrom a buried conformation (defined as DFG-in) to a solvent exposed conformation (defined as DFG-out).Although both experimental and computer simulation studies had been performed with the aim ofunveiling the details of the DFG-in to DFG-out transition, the molecular mechanism is still far from beingunequivocally depicted.Here, the accelerated molecular dynamics (AMD) technique has been applied to model the active loopflexibility of p38a and sample special protein conformations which can be accessible only in some conditionsor time periods. Starting from the assumption of an experimentally known initial and final state ofthe protein, the study allowed the description of the interaction network and the structural intermediateswhich lead the protein to change its loop conformation and active site accessibility. Besides a few importanthydrogen bond interactions, a primary role seems to be played by cation–p interactions, involvingthe DFG-loop residue F169, which participate in the stabilization of an intermediate conformation andin its consequent transition to the DFG-out conformation. From this study, insights which may prove usefulfor inhibitor design and/or site directed mutagenesis studies are derived.

2010 - Molecular Dynamics Simulations of Sodium Silicate Glasses:Optimization and Limits of the Computational Procedure [Articolo su rivista]
Pota, Marco; Pedone, Alfonso; Malavasi, Gianluca; Durante, Caterina; Cocchi, Marina; Menziani, Maria Cristina
abstract

The performance of the molecular dynamics (MD) simulations to obtain the structure of silica glasses containing different concentrations of alkali oxides has been tested. An optimal MD simulation procedure (including cooling cycle, MD constants and ensemble used) has been developed by means of experimental design methodologies (DOE), firstly restricting the study to the 30% Na2O silica glass for which experimental data are available to allow the comparison of the results. The optimization procedure led to simulations that well predict experimental density and short-range structure of glasses with different sodium content. On the contrary, the medium-range structure has been badly reproduced and it was not possible to determine a reliable correlation with the parameters of the simulation procedures used. Therefore, the correlation of medium-range properties with the structure has been studied by means of the PLS methods. The results showed to be useful to highlight the relationships among structural elements, such as radial distribution functions of specific bonds and angles, and Qn species, suggesting possible directions in order to improve the force field.

2010 - Multinuclear NMR of CaSiO3 Glass: Simulation from First-Principles [Articolo su rivista]
Pedone, Alfonso; T., Charpentier; Menziani, Maria Cristina
abstract

An integrated computational method which couples classical molecular dynamics simulations with density functional theory calculations is used to simulate the solid-state NMR spectra of amorphous CaSiO3. Two CaSiO3 glass models are obtained by shell-model molecular dynamics simulations, successively relaxed at the GGA-PBE level of theory. The calculation of the NMR parameters (chemical shielding and quadrupolar parameters), which are then used to simulate solid-state 1D and 2D-NMR spectra of silicon-29, oxygen-17 and calcium-43, is achieved by the gauge including projector augmented-wave (GIPAW) and the projector augmented-wave (PAW) methods. It is shown that the limitations due to the finite size of the MD models can be overcome using a Kernel Estimation Density (KDE) approach to simulate the spectra since it better accounts for the disorder effects on the NMR parameter distribution. KDE allows reconstructing a smoothed NMR parameter distribution from the MD/GIPAW data. Simulated NMR spectra calculated with the present approach are found to be in excellent agreement with the experimental data. This further validates the CaSiO3 structural model obtained by MD simulations allowing the inference of relationships between structural data and NMR response. The methods used to simulate 1D and 2D-NMR spectra from MD GIPAW data have been integrated in a package (called fpNMR) freely available on request.

2010 - New Insights into the Atomic Structure of 45S5 Bioglass byMeans of Solid-State NMR Spectroscopy and AccurateFirst-Principles Simulations [Articolo su rivista]
Pedone, Alfonso; T., Charpentier; Malavasi, Gianluca; Menziani, Maria Cristina
abstract

An integrated computational method that couples classical molecular dynamics simulations withdensity functional theory calculations has been used to simulate the solid-state 17O and 23NaMQMAS, 29Si, 31P, and 23Na static and MAS NMR spectra of the 45S5 Bioglass structural modelswith up to 248 atoms. Comparison with the experimental spectra collected in this work (the 17OMQMAS spectrum of the 45S5 Bioglass is reported for the first time in the literature) shows anexcellent agreement. The results provide deep insights into fundamental open questions regarding theatomic-scale structural details of this glass of great medical interest. In particular, the host silicanetwork, described by theQn distribution (aQn species is a network-forming ion bonded to n bridgingoxygens), consists of chains and rings ofQ2Si (67.2%) SiO4 tetrahedra cross-linked with Q3Si (22.3%)species and terminated by a low quantity of Q1Si (10.1%) species. No Si-O-P bridges have beendetected by both 31P NMR and 17O MQMAS experiments, and therefore isolated orthophosphateunits are able to form nanodomains that subtract sodium and calcium cations from their networkmodifying role into the silicate network. Finally, both the experimental and theoretical results show amixture of dissimilar cations (Na,Ca) around NBO, according to a nonrandom distribution of thesespecies.

2009 - Computational insight into the effect of CaO/MgO Substitution on the Structural Properties of Phospho-Silicate Bioactive Glasses. [Articolo su rivista]
Pedone, Alfonso; Malavasi, Gianluca; Menziani, Maria Cristina
abstract

The effect of the replacement of CaO for MgO on the structural properties of the 45S5 Bioglass with composition 46.2SiO2·24.3Na2O·(26.9 − x)CaO·2.6P2O5·xMgO where x = 0, 5, 10, 15, 20, and 26.9 mol has been studied by means of molecular dynamics simulations. The results confirmed the complexity of the local environment of Mg ions which are coordinated by 5 nonbridging oxygens of different TO4 tetrahedra (T = Si/P) leading to large rings in the structures. A rough correlation between the average dimension of the rings found in the structure and the computed Young’s modulus is obtained. The Young’s modulus decrease at low Mg-content reaching a minimum for the 46.2SiO2·24.3Na2O·16.9CaO·2.6P2O5·10MgO glass. At this composition, Mg is homogeneously distributed in the silica rich region together with Ca and Na ions but is almost totally absent from the Ca−Na-phosphate rich regions. The results suggest that the ideal glass composition for lowering the Young’s modulus preserving a specific bioactivity can be found below 10% of MgO content.

2009 - Progress Towards the Identification of New Aggrecanase Inhibitors [Articolo su rivista]
DE RIENZO, Francesca; Saxena, Puneet; Filomia, Federico; G., Caselli; F., Colace; L., Stasi; A., Giordani; Menziani, Maria Cristina
abstract

Degenerative diseases are still a challenging issue in clinical therapy; even though in several cases it is possible to treat symptoms, drugs able to block disease progression are lacking at present. Osteoarthritis (OA) and Rheumatoid Arthritis (RA) are degenerative diseases leading to serious cartilage destruction, affecting joint functions and giving rise to restricted movement, pain and chronic disability. Current clinical treatment for arthritis is confined to Non Steroidal Anti-Inflammatory Drugs (NSAIDs), which are effective in treating symptoms but fail to block the progression of the disease. Matrix Metalloproteases (MMPs) inhibitors have been clinically studied as possible drugs for cartilage degradation prevention. However, their clinical use has been limited by severe side-effects. Aggrecan, which plays a fundamental role in maintaining the structural and mechanical properties of cartilage, has recently been found to be specifically cleaved by "aggrecanases". Aggrecanases are multidomain zinc metalloproteases, different from MMPs, which cleave the aggrecan within the interglobular domain (IGD). Aggrecan breakdown at this site has been found to be crucial for cartilage degradation. These new findings re-addressed the interest of the research for new arthritis therapeutic agents focusing on aggrecanases rather than on MMPs. This review is meant to provide a critical appraisal of the ongoing developments of Zn-chelating and non chelating aggrecanase inhibitors, with a particular emphasis on the related structure-activity relationships (SARs), in the light of the protein structural information recently made available.

2009 - Quantitative Structure−Property Relationships of Potentially Bioactive Fluoro Phospho-silicate Glasses [Articolo su rivista]
Lusvardi, Gigliola; Malavasi, Gianluca; F., Tarsitano; Menabue, Ledi; Menziani, Maria Cristina; Pedone, Alfonso
abstract

In this work, the glass transition temperature and chemical durability of bioactive phospho-silicate glasses were experimentally determined and correlated to the structural descriptor Fnet derived from classical molecular dynamics simulations. The replacement of CaF2 for Na2O in the parent glass 45S5 enhances both chemical durability and density, while the replacement of CaF2 for CaO lowers chemical durability. The proposed descriptor, Fnet, provides satisfactorily correlations with glass transition temperature and chemical durability over a wide range of compositions.

2008 - A combined experimental-computational strategy for the design, synthesis and characterization of bioactive zinc-silicate glasses [Capitolo/Saggio]
Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina
abstract

This review presents a combined experimental-computational strategy for the development of potential bioactive zinc–containing silicate glasses and shows how sound relationships among the structural role of some key elements that appear to control bioactivity can by established and exploitfor rational glass design.

2008 - Accurate First-Principle Prediction of 29Si and 17O NMR Parameters in SiO2 Polymorphs: The Cases of Zeolites Sigma-2 and Ferrierite [Articolo su rivista]
Pedone, Alfonso; Pavone, M; Menziani, Maria Cristina; Barone, V.
abstract

Abstract: The magnetic shielding tensors of silica polymorphs have been investigated by meansof quantum chemical calculations. Several levels of theory, from Hartree-Fock to the lastgeneration of Density Functional Theory based approaches, have been tested on predicting29Si and 17O isotropic and principal components of the chemical shift tensors together with 17Oquadrupolar coupling constants. The NMR parameters have been computed on all known silicasystems, namely, R-quartz, R-cristobalite, coesite, Sigma-2, and ferrierite zeolites. Besides, clusterbased approaches have been compared to a hybrid Quantum-Mechanics/Molecular-Mechanics(QM/MM) method, within the ONIOM scheme. The convergence of computed 17O NMRparameters with respect to cluster size is found to be system-dependent. Excellent agreementbetween computed and experimental data has been found for 29Si NMR parameters of thedifferent Si sites of silica polymorphs and of Sigma-2 and ferrierite zeolites.

2008 - Elastic and dynamical properties of alkali silicate glasses from computer simulations techniques [Articolo su rivista]
Pedone, Alfonso; Malavasi, Gianluca; CORMACK A., N; Segre, Ulderico; Menziani, Maria Cristina
abstract

This paper shows recent progresses in the field ofcomputer simulations of inorganic glasses. Moleculardynamics simulations and energy minimization methods havebeen applied to calculate the elastic and transport proper-ties of alkali silicate glasses of compositions xM2 O · (100 −x)SiO2 (with x = 0, 10, 15, 20, 25, 30 % mol for M = Li,Na and K) and of a soda-lime glass with composition 15Na2 O·10CaO · 75SiO2 , which has been employed to ascertain theeffect of the replacement of CaO for Na2 O. The excellentagreement of the computed results with the experimentaldata highlights the important predictive and interpretativerole reached by computer simulations techniques.

2008 - Elucidation of the Structural Role of Fluorine in Potentially Bioactive Glasses by Experimental and Computational Investigation [Articolo su rivista]
Lusvardi, Gigliola; Malavasi, Gianluca; M., Cortada; Menabue, Ledi; Menziani, Maria Cristina; Pedone, Alfonso; Segre, Ulderico
abstract

Glasses belonging to the Na2O-CaO-P2O5-SiO2 system and modified by CaF2 substitution for CaO and Na2Oalternatively, were synthesized and characterized experimentally and computationally. The results of moleculardynamics simulations show that fluorine is almost exclusively bonded to modifier cations (Ca and Na) withcoordination number close to 4. A similar mean coordination number value is found in the crystal phasesobtained by means of thermal treatment at fixed temperature. Addition of fluorine increases the polymerizationof silicate tetrahedra by removing modifiers from the siliceous matrix. No appreciable amount of Si-F bondsare detected.

2008 - FFSiOH: a New Force Field for Silica Polymorphs and Their Hydroxylated Surfaces Based on Periodic B3LYP Calculations [Articolo su rivista]
Pedone, Alfonso; Malavasi, Gianluca; Segre, Ulderico; Menziani, Maria Cristina; Musso, F; Corno, M; Civalleri, B; Ugliengo, P.
abstract

A partial charge shell-ion model potential for silica polymorphs and their hydroxylated surfaces(FFSiOH) was parametrized in a self-consistent way using periodic B3LYP results for bulk R-cristobaliteand the (100) and (001) hydroxylated surfaces. The reliability of the new potentials was checked bycomparing structures, vibrational frequencies and relative phase stabilities of dense bulk silica polymorphs,namely R-quartz, R-cristobalite, R-tridymite, and Stishovite with both experimental and B3LYP data.The FFSiOH was also checked for computing structural and vibrational features of representative all-silica microporous materials, namely edingtonite, chabazite, and faujasite. As a last step, FFSiOH wasadopted to predict OH stretching vibrational frequencies and relative thermodynamic stability of themost common fully hydroxylated surfaces of the dense silica polymorphs, the (100) and (001) facesof all-silica edingtonite, the features of the local Si-defect in chabazite and sodalite known as (SiOH)4hydrogarnet and the geometries of H-bonded silanol groups of an amorphous silica surface. In all casesexcellent agreement resulted between FFSiOH and B3LYP periodic data and experimental data, whenavailable. The new FFSiOH force field opens up the molecular simulation of materials in which thesurface hydroxyl groups play a key role, as is the case for amorphous silica surfaces, all-silica zeoliteexternal surfaces, and the internal walls of mesoporous materials.

2008 - Medium-range order in phosphosilicate bioactive glasses: Insights from MAS-NMR spectra, chemical durability experiments and molecular dynamics simulations [Articolo su rivista]
L., Linati; Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; P., Mustarelli; Pedone, Alfonso; Segre, Ulderico
abstract

The medium-range order of phospho-silicate bioactive glasses (with compositions (2 p)SiO2 Æ 1Na2O Æ 1.1CaO Æ pP2O5, in whichp = 0.10, 0.20, 0.26) has been studied by means of a combined-experimental (MAS-NMR, chemical durability measurements) and computational(classical molecular dynamics (MD)) approach. The structural model obtained by MD is showed to be helpful in the interpretationof the NMR spectra. A small amount of Si–O–P link units has been detected in glasses with low P2O5-content, but at high P2O5concentration the percentage of Si–O–P bridges becomes important. However, Qn distributions show that the HP5 (p = 0.20) glass structureis less polymerized with respect to the H (p = 0.10) and HP6.5 (p = 0.26) glasses. These results provide useful explanation of thebehavior of these glasses in water and highlight the influence of the medium-range order on a very important property of potentialbioactive glasses such as the chemical durability.

2008 - Molecular dynamics of stress-strain behaviour of silica glass under tensile load. [Articolo su rivista]
Pedone, Alfonso; Malavasi, Gianluca; Menziani, Maria Cristina; Segre, Ulderico; Cormack, A. N.
abstract

Molecular dynamics (MD) simulations were carried out to study the stress-strain diagrams of crystallineand amorphous silica under different nonequilibrium conditions. The responses of a tensile load wererecorded in two cases. In one case, the system was not allowed to relax along the transverse direction(null Poisson’s ratio), while in the other case, the deformations were allowed in directions perpendicularto the strained one. The higher strength of crystalline silica as compared to amorphous silica resultedfrom a different distribution of ring sizes. The results obtained for the inert failure strains and intrinsicstrength of the silica glass were in good agreement with the experimental data, and the nonlinear elasticbehavior of the glass was reproduced along with the effects of strain rate and temperature variation.Elastic properties extracted from stress-strain diagrams also were compared with the properties calculatedby means of static methods and with experimental data.

2008 - Properties of zinc releasing surfaces for clinical applications [Articolo su rivista]
Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; Pedone, Alfonso; Segre, Ulderico; Aina, V; Perardi, A; Morterra, C; Boccafoschi, F; Gatti, S; Bosetti, M; Cannas, M.
abstract

Two series of glasses of general formula (2-p) SiO21.1Na2OCaOpP2O5xZnO (p = 0.10, 0.20; x = 0.0, 0.16, 0.35, and 0.78) have been analyzed for physico-chem. surface features before and after contact with simulated body fluid, morphol. characteristics, and osteoblast-like cells behavior when cultured on them. The resulted good cell adhesion and growth, along with nonsignificant changes of the focal contacts, allow the authors to indicate HZ5 and HP5Z5 glasses as the ones having optimal ratio of Zn/P to maintain acceptable cell behavior, comparable to the bioactive glass (Bioglass) used as a control; results are also rationalized by means of three-dimensional models derived by mol. dynamic simulations, with decompn. and conversion rates optimized with respect to the parent Hench's Bioglass.

2008 - Role of Magnesium in Soda-Lime Glasses: Insight into Structural, Transport, and Mechanical Properties through Computer Simulations [Articolo su rivista]
Pedone, Alfonso; Malavasi, Gianluca; Menziani, Maria Cristina; Segre, Ulderico; Cormack, A. N.
abstract

The role of Mg in soda-lime glasses was elucidated by classical molecular dynamics (MD) simulations. Theeffect of the replacement of CaO for MgO on the structure, transport, and elastic properties of a series ofglasses with compositions 15Na2O · (10 - x)CaO · xMgO · 75SiO2 (x ) 0, 5, and 10 mol) was studied. Differentstructural roles were found for the Ca and Mg ions. The former, coordinated by six oxygen atoms, acts as anetwork modifier, while the latter, four-fold coordinated, participates in the silica network. Consequently, Naion diffusion is favored by the replacement of MgO for CaO in these glasses, as shown by variation in thecomputed diffusion coefficients and activation energy of the process in the series of glasses studied. Moreover,the consequences of these structural modifications on the elastic properties (Young’s modulus, shear modulus,bulk modulus, Poisson’s ratio, and compressibility) of the glasses were evaluated by means of energyminimization techniques carried out on the structures obtained by MD simulations.

2007 - A computational multiscale strategy of the study of amorphous materials [Articolo su rivista]
Malavasi, Gianluca; Menziani, Maria Cristina; Pedone, Alfonso; Civalleri, B; Corno, M; Ugliengo, P.
abstract

A first step towards a computational Si–O–P angles, respectively. Other geometrical featuresmultiscale approach has been adopted here to deal with are in excellent agreement within the two approaches.the computational simulation of the Hench bioglass Electronic properties of the Hench bioglass have been45S5, an amorphous material of 48.1% SiO2 , 25.9% reported at B3LYP for the first time and both Mullik-CaO, 22.2% Na2 O and 3.7% P2 O5 composition. Molec- en charges and electronic band structure show a ratherular dynamics simulations based on classical force fields ionic character of the material, whereas a band gap offollowed by static minimizations on quenched structures about 6.5 eV characterizes the bioglass as a strong insu-have been run on a unit cell size suitable for subsequent lator. Work presently in progress will soon allow theab initio calculations. The molecular mechanics opti- information to be transferred from the B3LYP calcu-mized unit cell envisaging 78 atoms of Na12 Ca7 P2 Si13 lations to the molecular mechanics engine in order toO44 composition and P1 symmetry has then been fully refine the presently available empirical force fields foroptimized (both unit cell parameters and internal coor- complex ionic systems and their surfaces.dinates) at B3LYP level in a periodic approach usinggaussian basis sets of double-ζ quality and the devel-opment version of the CRYSTAL03 code. Comparisonbetween the molecular mechanics and B3LYP optimizedstructures shows the latter to give a slightly higherdensity than the former, due to overestimation of theSi–O bonds and underestimation of the Si–O–Si and

2007 - An ab initio parameterized interatomic force field for hydroxyapatite [Articolo su rivista]
Pedone, Alfonso; M., Corno; B., Civalleri; Malavasi, Gianluca; Menziani, Maria Cristina; Segre, Ulderico; P., Ugliengo
abstract

A classical interatomic force field for hydroxyapatite has been parameterized from periodicab initio calculations carried out on the hexagonal structure (space group P63). The GULPprogram has been used for fitting geometry and phonon frequencies computed with theCRYSTAL06 program using the B3LYP hybrid functional and Gaussian-type basis set ofpolarized double zeta quality. Polarization effects and covalent bonding have been includedthrough the shell-ion model potential. Excellent agreement has been found in reproducingstructural features, lattice dynamics, the OH stretching vibrations and relative phase stabilitiesbetween the monoclinic structure (space group P21/b) and the hexagonal one. Transferability fromhydroxyapatite to other calcium phosphates has also been demonstrated.

2007 - Crystallization Kinetics of Bioactive Glasses in the ZnO-Na2O-CaO-SiO2 System [Articolo su rivista]
Malavasi, Gianluca; Lusvardi, Gigliola; Pedone, Alfonso; Menziani, Maria Cristina; M., Dappiaggi; Gualtieri, Alessandro; Menabue, Ledi
abstract

The crystallization kinetics of Na2OâCaOâ2SiO2 (x ) 0) and 0.68ZnOâNa2OâCaOâ2SiO2 (x ) 0.68, where xis the ZnO stoichiometric coefficient in the glass formula) bioactive glasses have been studied using bothnonisothermal and isothermal methods. The results obtained from isothermal XRPD analyses have showedthat the first glass crystallizes into the isochemical Na2CaSi2O6 phase, whereas the Na2ZnSiO4 crystallinephase is obtained from the Zn-rich glass, in addition to Na2CaSi2O6. The activation energy (Ea) for thecrystallization of the Na2OâCaOâ2SiO2 glass is 193 ( 10 and 203 ( 5 kJ/mol from the isothermal in situXRPD and nonisothermal DSC experiments, respectively. The Avrami exponent n determined from theisothermal method is 1 at low temperature (530 °C), and its value increases linearly with temperature increaseup to 2 at 607 °C. For the crystallization of Na2CaSi2O6 from the Zn-containing glass, higher values of boththe crystallization temperature (667 and 661 °C) and Ea (223 ( 10 and 211 ( 5 kJ/mol) have been foundfrom the isothermal and nonisothermal methods, respectively. The Na2ZnSiO4 crystalline phase crystallizesat lower temperature with respect to Na2CaSi2O6, and the Ea value is 266 ( 20 and 245 ( 15 kJ/mol fromthe isothermal and nonisothermal methods, respectively. The results of this work show that the addition ofZn favors the crystallization from the glass at lower temperature with respect to the Zn-free glass. In fact, itcauses an increase of Ea for the Na diffusion process, determined using MD simulations, and consequentlyan overall increase of Ea for the crystallization process of Na2CaSi2O6. Our results show good agreementbetween the Ea and n values obtained with the two different methods and confirm the reliability of thenonisothermal method applied to kinetic crystallization of glassy systems. This study allows the determinationof the temperature stability field of the crystalline phases with the view of creating a different glass ceramicuseful in the field of bioactive materials.

2007 - Density of multicomponent silica-based potential bioglasses: Quantitative structure-property relationships (QSPR) analysis [Articolo su rivista]
Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; Pedone, Alfonso; Segre, Ulderico
abstract

The results of a quantitative structure-property relationships (QSPR) analysis of multicomponent silica-based potential bioglasses (containing Na2O, CaO, P2O5 and/or ZnO) are here presented. A quantitative model explaining the variation of the density data measured for series of glasses with different compositions has been obtained by means of a structural descriptor derived from molecular dynamics (MD) simulations. A descriptor able to rationalize the variation in density caused by the overall packing degree of the structural units in the glasses examined has been defined. It is worth noting that the descriptor used allows the fitting of glasses with different composition (presence-absence Of P2O5, ZnO, Na2O and CaO) in the same correlation. The validity of the QSPR approach, which has recently been introduced for the rationalization and prediction of the technology-related properties of a series of complex multicomponent glasses, is confirmed by this work on a larger series of glasses of various compositions. (c) 2006 Elsevier Ltd. All rights reserved.

2007 - Insight into elastic properties of binary alkali silicate glasses; prediction and interpretation through atomistic simulation techniques [Articolo su rivista]
Pedone, Alfonso; Malavasi, Gianluca; A. N., Cormack; Segre, Ulderico; Menziani, Maria Cristina
abstract

Molecular dynamics simulations and energy-minimization techniques have been applied for the firsttime to determine the whole set of elastic properties (Young’s modulus, shear modulus, bulk modulus,and Poisson’s ratio) of alkali silicate glasses with different ion modifiers (Li, Na, and K) in the range0-30 mol % alkaline oxide. Excellent agreement has been found between the simulation results and theexperimental data. The peculiar behavior of the Li-containing glasses with respect to the Na and K onesis extensively discussed in terms of the glass structural features. It is found that the elastic propertyvariation as a function of alkali addition can be explained by three concurrent factors: (1) depolymerizationof the silica network; (2) increasing the cohesion of the glass by the establishment of alkali-NBO bonds;and (3) decreasing the free volume with consequent increasing of the glass packing density.

2006 - A computational protocol to probe the role of solvation effects on the reduction potential of azurin mutants [Articolo su rivista]
V., Barone; DE RIENZO, Francesca; E., Langella; Menziani, Maria Cristina; N., Rega; Sola, Marco
abstract

Semiquantitative relationships between thermodynamic parameters of Cu2+ reduction experimentally measured for a series of azurin mutants and the solvation free energy of the oxidized state of the proteins were derived. Solvation free energy calculations were carried out within an ONIOM/PCM scheme specifically adapted to this protein series. The method proved to be able to capture the main determinants of the measured reduction parameters, providing satisfactory predictions of the E degrees'.

2006 - A new self-consistent empirical interatomic potential model for oxides, silicates, and silica-based glasses [Articolo su rivista]
Pedone, Alfonso; Malavasi, Gianluca; Menziani, Maria Cristina; An, Cormack; Segre, Ulderico
abstract

A new empirical pairwise potential model for ionic and semi-ionic oxides has been developed. Its transferability and reliability have been demonstrated by testing the potentials toward the prediction of structural and mechanical properties of a wide range of silicates of technological and geological importance. The partial ionic charge model with a Morse function is used, and it allows the modeling of the quenching of melts, silicate glasses, and inorganic crystals at high-pressure and high-temperature conditions. The results obtained by molecular dynamics and free energy calculations are discussed in relation to the prediction of structural and mechanical properties of a series of soda lime silicate glasses.

2006 - Cell configuration for focal adhesions in cells seeded onto Zinc-doped silicate-bioglasses [Capitolo/Saggio]
Lusvardi, Gigliola; Malavasi, Gianluca; Pedone, Alfonso; Menabue, Ledi; Menziani, Maria Cristina; V., Bolis; M., Borsetti; F., Boccafoschi; M., Cannas
abstract

2006 - Physico-chemical characterization and in vivo evaluation of zinc-glasses biocompatibility [Capitolo/Saggio]
Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; Pedone, Alfonso; Zaffe, Davide
abstract

Study of soda-lime-phosphosilicate glasses based on Bioglass® and modified by zinc. "In vitro"(SBF) bioactivity was investigated through apatite forming ability and through a preliminary "in vivo" study. Zinc improves chemical durability but does not inhibit the apatite formation; a mixed-metal (Ca-Zn) phosphate-based crystalline layer is identified on the surface of HP5Z5. The improvement of the observed chemical durability can also be rationalized by Molecular Dynamics simulations

2006 - Structure-activity relationships of hydroxylated flavone derivatives and their inhibitory action over human cytochrome P450 1A2 [Articolo su rivista]
R., DA FONSECA; A., Melo; Iori, Francesco; Menziani, Maria Cristina; M. J., Ramos
abstract

Activation by human cytochrome P450 1A2 (hCYP1A2) of heterocyclic amines is assumed to trigger of a number of carcinogenic processes. In this work, a group of natural inhibitors of human cytochrome P450 1A2 reported in literature has been theoretically analysed. These consist of flavone hydroxylated derivatives, natural compounds that exist in plants and associated products. Different theoretical/computational tools were used to describe the specific molecular interactions between these compounds and hCYP1A2. Based on this analysis, a method is proposed for helping the selection of specific molecular features that enhance protein-inhibitor interaction.

2006 - Towards a quantitative rationalization of multicomponent glass properties by means of molecular dynamics simulations [Articolo su rivista]
Malavasi, Gianluca; Pedone, Alfonso; Menziani, Maria Cristina
abstract

This review summarizes the achievements obtained by making use of molecular dynamics (MD) simulations in the elucidation of the structure of multicomponent glasses exerting bioactive properties. Emphasis on critical aspects of MD simulations for oxide glasses treatment is given. The potentiality of the quantitative structure-property relationships (QSPR) analysis as a tool for interpretative and predictive purposes is highlighted.

2006 - Void size distribution in MD-modelled silica glass structures [Articolo su rivista]
Malavasi, Gianluca; Menziani, Maria Cristina; Pedone, Alfonso; Segre, Ulderico
abstract

The void distribution of different models of the silica glass have been analyzed in terms of the Voronoi-Delaunay description of the void space into a disordered system. The silica glass has been modelled by making use of different pair-pair and three body potentials, previously proposed. The glass structural parameters (bond lengths and bond angles) are compared with known experimental data. A computer algorithm has been implemented to apply the Voronoi-Delaunay approach to a system of non-uniform spheres, and it is fully described. The algorithm furnishes the size distribution of interstices into the bulk structure. From this result, the solubility of noble gasses into the glass is computed, and the values obtained are successfully compared to known experimental data. The correlation between void size distribution and ring size distribution in silica glass is discussed. Both the glass structure and void distribution give better agreement to the experimental data when the pair pair interaction is modelled with the potential developed by Beest et al. [B.W.H. Beest, G.J. Kramer, R.A. Santen, Phys. Rev. Lett. 64 (1990) 1955].

2005 - A Computational Tool for the Prediction of Crystalline Phases Obtained from Controlled Crystallization of Glasses [Articolo su rivista]
Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; Pedone, Alfonso; Segre, Ulderico
abstract

An automatic tool (named CLUSTER) for the prediction of the most probable crystal phases that can separatefrom glasses has been developed. The program analyzes the output of molecular dynamics simulations ofglasses or glass ceramics, systematically sampling the ratios of the ions in different portions of the simulationbox and comparing them to the stoichiometric ratio of compositionally equivalent crystalline phases retrievedfrom a crystal structure database. The efficacy of the similarity index elaborated has been judged by comparingthe results obtained with the crystal phases identified by XRD analysis after thermal treatment in a series ofmulticomponent potential bioactive glasses and glass ceramics for which the advantages of rational-designederosion-controlled release is straightforward.

2005 - Computational insight into anti-mutagenic properties of CYP1A flavonoid ligands [Articolo su rivista]
R., DA FONSECA; Marini, Michele; A., Melo; Menziani, Maria Cristina; MARIA J., Ramos
abstract

Cytochrome P450 1A (CYP1A) is a subclass of enzymes involved in the biotransformation of heterocyclic amines, which are present in cooked red meat, to carcinogenic compounds. Anti-cancer properties have long been associated with flavonoids, and some compounds of this class have been shown to interact directly with CYP1A2. The understanding of this interaction is the purpose of this work. As the number of experimentally tested molecules is limited, a method is proposed for the study of protein-inhibitor interaction as an alternative to a QSAR analysis, using molecular mechanics force-fields.

2005 - Further studies on the interaction of the 5-hydroxytryptamine(3) (5-HT3) receptor with arylpiperazine ligands. Development of a new 5-HT3 receptor ligand showing potent acetylcholinesterase inhibitory properties [Articolo su rivista]
A., Cappelli; A., Gallelli; M., Manini; M., Anzini; L., Mennuni; F., Makovec; Menziani, Maria Cristina; S., Alcaro; F., Ortuso; S., Vomero
abstract

Novel arylpiperazine derivatives bearing lipophilic probes were designed, synthesized, and evaluated for their potential ability to interact with the 5-hydroxytryptamine(3) (5-HT3) receptor. Most of the new compounds show subnanomolar 5-HT3 receptor affinity. Ester 6bc showing a picomolar K-i value is one of the most potent 5-HT3 receptor ligands so far synthesized. The structure-affinity relationship study suggests the existence of a certain degree of conformational freedom of the amino acid residues interacting with the substituents in positions 3 and 4 of the quipazine quinoline nucleus. Thus, the tacrine-related heterobivalent ligand 6o was designed in an attempt to capitalize on the evidence of such a steric tolerance. Compound 6o shows a nanomolar potency for both the 5-HT3 receptor and the human AChE and represents the first example of a rationally designed high-affinity 5-HT3 receptor ligand showing nanomolar AChE inhibitory activity. Finally, the computational analysis performed on compound 6o allowed the rationalization of the structure-energy determinants for AChE versus BuChE selectivity and revealed the existence of a subsite at the boundary of the 5-HT3 receptor extracellular domain, which could represent a peripheral site similar to that evidenced in the AChE gorge.

2005 - Qualitative and quantitative structure-property relationships analysis of multicomponent potential bioglasses [Articolo su rivista]
L., Linati; Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; P., Mustarelli; Segre, Ulderico
abstract

The results of a qualitative and quantitative structure-property relationships analysis of multicomponent potential bioglasses of composition (2 - y)SiO(2)center dot 1Na(2)O center dot 1.1CaO center dot yP(2)O(5)center dot xZnO (x = 0, 0.16, 0.35, 0.78 and y - 0. 10, 0.20, 0.36) are presented. Quantitative models are obtained by means of structural descriptors derived by molecular dynamics simulations and experimental data measured for density, thermal analysis, 21 Si and IT magic angle spinning NMR, and chemical durability in water. Analysis of the crystal species obtained upon glass crystallization helped in the rationalization of the structural role of the different components. Finally, glass surface characterization with scanning electron microscopy, transmission electron micrsocopy, and X-ray diffraction after soaking in acellular simulated body fluid demonstrated the in vitro bioactivity of the newly obtained 1.80SiO(2)center dot 1Na(2)O center dot 1.1Ca center dot 0.20P(2)O(5)center dot 0.16ZnO (HP5Z5) glass, corresponding to x = 0. 16 and y = 0.20.

2005 - Theoretical quantitative structure-activity relationships of flavone ligands interacting with cytochrome P450 1A1 and 1A2 isozymes [Articolo su rivista]
Iori, Francesco; R., da Fonseca; M. J., Ramos; Menziani, Maria Cristina
abstract

Theoretical descriptors obtained from quantum mechanical calculations on isolated ligands in different media and molecular dynamics simulations of ligand-enzyme complexes have been used to obtain a quantitative rationalization of the inhibition of CYP1A2 and CYP1A2 by three series of flavonoids. Predictive models obtained through one-descriptor QSAR studies and mechanistic explanations have been obtained for recognition and selectivity.

2005 - Zinc-releasing silicate-bioglasses modulated Bone Cells Activity [Relazione in Atti di Convegno]
Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; Segre, Ulderico; V., Aina; C., Morterra; M. F., Cannas
abstract

Two series of glasses of general formula (2-p) SiO21.1Na2OCaOpP2O5xZnO ( p ¼ 0.10, 0.20; x ¼ 0.0, 0.16, 0.35, and 0.78) have been analyzed for physico-chemical surface features before and after contact with simulated body fluid, morphological characteristics, and osteoblastlike cells behavior when cultured on them. The resulted good cell adhesion and growth, along with nonsignificant changes of the focal contacts, allow the authors to indicate HZ5 and HP5Z5 glasses as the ones having optimal ratio of Zn/P to maintain acceptable cell behavior, comparable to the bioactive glass (Bioglass) used as a control; results are also rationalized by means of three-dimensional models derived by molecular dynamic simulations, with decomposition and conversion rates optimized with respect to the parent Hench’s Bioglass

2004 - A combined experimental and computational approach to (Na2O)(1-x) (CaO) (ZnO)(x)2SiO2 glasses characterization [Articolo su rivista]
Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; Segre, Ulderico; M. M., Carnasciali; A., Ubaldini
abstract

Insight into the Zn structural role in a series of glasses of composition (Na2O)(1-x) (.) CaO (.) (ZnO)(x) (.) 2SiO(2) (x = 0, 0.2, 0.6 and 1) has been obtained by density measurements, analysis of the crystals separated from the glasses, micro-Raman spectra and molecular dynamics simulations. We found that Zn acts as a weak tetrahedral network former independent of the glass Na content.

2004 - CaO and ZnO in soda-silicate glasses: a molecular dynamics simulation study and experimental characterization [Capitolo/Saggio]
Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; Segre, Ulderico
abstract

CaO and ZnO in soda-silicate glasses: a molecular dynamics simulation study and experimental characterization

2004 - Computational approaches to structural and functional analysis of plastocyanin and other blue copper proteins [Articolo su rivista]
DE RIENZO, Francesca; Rr, Gabdoulline; Rc, Wade; Sola, Marco; Menziani, Maria Cristina
abstract

Computational techniques are becoming increasingly important in structural and functional biology, in particular as tools to aid the interpretation of experimental results and the design of new systems. This review reports on recent studies employing a variety of computational approaches to unravel the microscopic details of the structure-function relationships in plastocyanin and other proteins belonging to the blue copper superfamily. Aspects covered include protein recognition, electron transfer and protein-solvent interaction properties of the blue copper protein family. The relevance of integrating diverse computational approaches to address the analysis of a complex protein system, such as a cupredoxin metalloprotein, is emphasized.

2004 - Design, Synthesis, Strucural Studies, Biological Evaluation, and Computational Simulations of Novel Potent AT1 Angiotensin II Receptor Antagonists Based on the 4-Phenylquinoline Structure [Articolo su rivista]
A., Cappelli; G. P., Mohr; A., Gallelli; M., Rizzo; M., Anzini; S., Vomero; L., Mennuni; F., Ferrari; F., Makovec; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; G., Giorgi
abstract

Novel AT1 receptor antagonists bearing substituted 4-phenylquinoline moieties instead of theclassical biphenyl fragment were designed and synthesized as the first step of an investigationdevoted to the development of new antihypertensive agents and to the understanding of themolecular basis of their pharmacodynamic and pharmacokinetic properties. The newlysynthesized compounds were tested for their potential ability to displace [125I]Sar1,Ile8-Ang IIspecifically bound to AT1 receptor in rat hepatic membranes. These AT1 receptor binding studiesrevealed nanomolar affinity in several of the compounds under study. The most potent ligands4b,t were found to be equipotent with losartan and possessed either a 3-tetrazolylquinoline ora 2-amino-3-quinolinecarboxylic moiety, respectively. Moreover, some selected compounds wereevaluated for antagonism of Ang II-induced contraction in rabbit aortic strips, and the mostpotent compounds in the binding test 4b,t were slightly more potent than losartan in inhibitingAng II-induced contraction. Finally, the most relevant structure-affinity relationship data wererationalized by means of computational studies performed on the isolated ligands as well asby computational simulations on the ligands complexed with a theoretical AT1 receptor model.

2004 - Synthesis and in vitro studies of phosphosilicate glasses doped with cerium and zinc oxides [Articolo su rivista]
Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; Segre, Ulderico
abstract

Glasses based on the Bioglass, formula and doped by the addn. of CeO2 (1.5-13.5%) and ZnO (5-20%) were studied. The addn. if small oxide quantities (1.5% for CeO2 and 5-10% for ZnO) did not significantly alter the ability of the in vitro apatite formation on the glass surface. After 15 days, a mixed-metal (Ca-Zn) or (Ca-Ce) phosphate-based layer was identified. High metal contents improved the chem. durability of the glass, the bioactivity was strongly inhibited and there were no hints of apatite formation obsd. even after prolonged soaking in SBF. The SiO2, 39.4; Na2O, 22.6; CaO, 22.6; P2O5, 10.4; ZnO, 5.0% glass compn. seems to demonstrate an optimal ratio of Zn/P to improve the glass strength and simultaneously yield a Ca/P ratio able to preserve rapid apatite formation.

2004 - Vetri bioattivi contenenti zinco: comportamento in viotro ed in vivo [Relazione in Atti di Convegno]
Lusvardi, Gigliola; Zaffe, Davide; Bertoldi, Carlo; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina; Pedone, Alfonso
abstract

Vedi allegato

2003 - Development of an IL-6 antagonist peptide that induces apoptosis in IL-6 dependent 7TD1 cells. [Articolo su rivista]
Manfredini, Rossella; Tenedini, Elena; M., Siena; Tagliafico, Enrico; Montanari, Monica; Grande, Alexis; ZANOCCO MARANI, Tommaso; C., Poligani; Zini, Roberta; A., Bergamaschi; DE RIENZO, Francesca; DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Ferrari, Sergio
abstract

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in the regulation of proliferation and differentiation of hematopoietic cells and in the pathogenesis of many diseases, including multiple myeloma. This study pursues a way to interfere with IL-6 pathway in an attempt to modulate its biological activity. Here we describe the rational design and biological evaluation of peptides able to antagonize the murine IL-6 activity by interfering with IL-6 Receptor alpha in 7TD1 cells, a IL-6-dependent B-cell line. Of the peptide tested, only Guess 4a is capable of interfering with IL-6 transducing pathway, therefore inducing growth arrest and apoptosis of 7TD1 cells.

2003 - Modelling the metabolic action of human and rat CYP1A2 and its relationship with the carcinogenicity of heterocyclic amines [Articolo su rivista]
R., DA FONSECA; Menziani, Maria Cristina; A., Melo; Mj, Ramos
abstract

Cytochrome P450 (CYP) is a family of enzymes responsible for organism detoxification. However, some of the members of the CYP1A subfamily also catalyse the activation of heterocyclic amines (HAs), present in cooked meat, to carcinogenic compounds which have been shown to increase the risk of breast, colorectal and lung cancer. In humans, CYP1A2 is the enzyme with the most significant action in HA metabolism but in rodents CYP1A1 is also important in this biotransformation. Understanding the metabolic action of these enzymes is essential to predict the factors that enable the formation of the carcinogenic products. We have built two models of CYP1A2, one for the human enzyme and one for the rat homologue. The templates chosen include the only X-ray structure published to date for a mammal CYP, a quimeric C2A5 from rabbit, as well as CYPs belonging to Bacillus megaterium (CYPBm-3), Pseudomonas putida (CYPcam), Pseudomonas sp. (CYPterp), and Saccharopolyspora erythraea (CYPeryf). Two HAs, MeIQ (2-amino-3,4-dimethylimidazo[4,5-f] quinoline) and MeIQx (2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline), known substrates of human and rat CYPIA2, were docked in the active site of the models, providing information regarding the different catalytic rates associated with the metabolisms in both enzymes. This is important for analysing the behaviour of animal models concerning the testing of anticancer drugs.

2003 - Seeking for binding determinants of the prion protein to human plasminogen [Articolo su rivista]
Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; E., Langella; V., Barone
abstract

Plasminogen (Pg), a pro-protease implicated in neuronal excitotoxicity, has recently been identified as binding to prion protein (PrP) from several species. Although the precise effect of the binding of PrP to plasminogen in the course of prion-caused diseases has not yet been demonstrated, the implications of this important finding for diagnostic applications are straightforward. In this paper we have investigated the possible modes of interaction of PrP with plasminogen, by means of molecular modelling and computational simulation techniques. To this goal, we first exploited the information available for the mK2(Pg)/VEK-30 complex in order to identify the PrP residues which satisfy the specific electronic and geometric requirements needed to interact with the kringle lysine binding site, we compared the relevant mK2(Pg)/VEK-30 and mK2(Pg)/PrP interactions obtained from the simulated protein-protein complexes and we assessed the docking hypothesis utilized for the mK2(Pg)/PrP complex by simulating the interaction of PrP with the multi-kringle angiostatin, a more realistic model of the physiological target. The results obtained will be instrumental for planning experiments tailored to clarify the role of the plasminogen activator system in prion-related diseases and, eventually, for mimicking dominant binding determinants through structure-based drug design.

2003 - Synthesis, biological evaluation, and receptor docking simulations of 2-[(acylamino)ethyl]-1,4-benzodiazepines as kappa-opioid receptor agonists endowed with antinociceptive and antiamnesic activity [Articolo su rivista]
M., Anzini; L., Canullo; C., Braile; A., Cappelli; A., Gallelli; S., Vomero; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; M., Rizzo; S., Collina; O., Azzolina; M., Sbacchi; C., Ghelardini; N., Galeotti
abstract

The synthesis and biological evaluation of a series of new derivatives of 2-substituted 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), are reported. Chemical and pharmacological studies on compounds 6 have been pursued with the aim of expanding the SAR data and validating the previously proposed model of interaction of this class of compounds with the kappa-opioid receptor. The synthesis of the previously described compounds 6 has been reinvestigated in order to obtain a more direct synthetic procedure. To study the relationship between the stereochemistry and the receptor binding affinity, compounds 6e and 6k were selected on the basis of their evident structural resemblance to tifluadom. Since a different specificity of action could be expected for the enantiomers of 6e and 6k, owing to the results shown by (S)- and (R)-tifluadom, their racemic mixtures have been resolved by means of liquid chromatography with chiral stationary phases (CSP), and the absolute configuration of the enantiomers has been studied by circular dichroism (CD) and H-1 NMR techniques. Moreover, some new 2-[(acylamino)ethyl]-1,4-benzodiazepine derivatives, 6a-d,f,g,j, have been synthesized, while the whole series (6a-o) has been tested for its potential affinity toward human cloned kappa-opioid receptor. The most impressive result obtained from the binding studies lies in the fact that this series of 2-[2-(acylamino)ethyll-1,4-benzodiazepine derivatives binds the human cloned kappa-opioid receptor subtype very tightly. Indeed, almost all the ligands within this class show subnanomolar K-i values, and the least potent compound 6o shows, in any case, an affinity in the nanomolar range. A comparison of the affinities obtained in human cloned kappa-receptor with the correspondent one obtained in native guinea pig kappa-receptor suggests that the human cloned kappa-receptor is less effective in discriminating the substitution pattern than the native guinea pig kappa-receptor. Furthermore, the results obtained are discussed with respect to the interaction with the homology model of the human kappa-opioid receptor, built on the recently solved crystal structure of rhodopsin. Finally, the potential antinociceptive and antiamnesic properties of compounds 6e and 6i have been investigated by means of the hot-plate and passive avoidance test in mice, respectively.

2003 - Zinc addition to sodium-calcium-silicate bioglasses. Theoretical vs experimental results [Capitolo/Saggio]
Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina
abstract

The glass composition Na2O•CaO•2SiO2 was modified upon addition of ZnO to obtain the series of glasses Na2O•CaO•(2-x)SiO2•xZnO (x=0.15 and 0.19), where x= 0.19 is the maximum zinc content which does not produce phase separation. The glasses were investigated by means of density and thermal measurements (glass transition, Tg, and crystallisation, Tc, temperature); moreover the phases separated upon crystallisation were identified. The results of molecular dynamics (MD) simulations combined with the analysis of the crystal structure of the main phases separated [(Na4Ca4(SiO3)6 and Na2ZnSiO4)] provide insight into the structural role of zinc in the glass network, its limits of solubility and its effect on the short- and medium-range order of the glass structure.

2002 - Biologically relevant properties of copper-containing proteins analysed by means of semi-quantitative and quantitative theoretical descriptors [Capitolo/Saggio]
DE RIENZO, Francesca; R. R., Gabdoulline; R. C., Wade; Menziani, Maria Cristina
abstract

Biologically relevant properties of copper-containing proteins analysed by means of semi-quantitative and quantitative theoretical descriptors

2002 - Erratum: "Novel potent 5-HT3 receptor ligands based on the pyrrolidone structure. Effects of the quaternization of the basic nitrogen on the interaction with 5-HT3 receptor" (Bioorganic and Medicinal Chemistry (2002) 10 (2681) PII: S0968089602000937) [Altro]
Cappelli, A.; Gallelli, A.; Braile, C.; Anzini, M.; Vomero, S.; Mennuni, L.; Makovec, F.; Menziani, Maria Cristina; De Benedetti, P. G.; Donati, A.; Giorgi, G.
abstract

Errata corrige

2002 - Experimental versus computer simulation analysis of zirconia containing glasses [Relazione in Atti di Convegno]
Montorsi, Monia; Menziani, Maria Cristina; Siligardi, Cristina; Manfredini, Tiziano; A. N., Cormack
abstract

The addition of zirconia to lime silicate glasses produces consistent glass structure modifications which can be consider directly responsible of the improvement in chemical resistance, optical, thermal and mechanical properties of the glass. Therefore, this class of materials represents an interesting topics in science and material engineering, especially as concerning the design and development of new glass materials for industrial applications. In this work, molecular dynamic simulations have been used to complement the glass structure characterisation experimentally determined and to correlate the structural modifications induced by zirconia in the glass network to the chemical and physical properties macroscopically measured for the CaO-ZrO2-SiO2 system.

2002 - Molecular Dynamics Study of Zirconia Containing Glasses [Articolo su rivista]
Montorsi, Monia; Menziani, Maria Cristina; Leonelli, Cristina; J., Du; A. N., Cormack
abstract

Molecular Dynamics Study of Zirconia Containing Glasses

2002 - Novel 5-HT(3) receptor ligands based on the pyrrolidone structure: synthesis, biological evaluation, and computational rationalization of the ligand-receptor interaction modalities [Articolo su rivista]
A., Cappelli; M., Anzini; S., Vomero; L., Mennuni; F., Makovec; E., Doucet; M., Hamon; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; G., Giorgi; C., Ghelardini; S., Collina
abstract

Novel 5-HT(3) receptor ligands based on the pyrrolidone structure: synthesis, biological evaluation, and computational rationalization of the ligand-receptor interaction modalities

2002 - Novel potent 5-HT3 receptor ligands based on the pyrrolidone structure. Effects of the quaternization of the basic nitrogen on the interaction with 5-HT3 receptor [Articolo su rivista]
A., Cappelli; A., Gallelli; C., Braile; M., Anzini; S., Vomero; L., Mennuni; F., Makovec; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; A., Donati; G., Giorgi
abstract

The results of a comprehensive structure-affinity relationship study on the effect of the quaternization (i.e., N-methylation) of structurally different ligands in the classes of tropane and quinuclidine derivatives are described. This study shows that the effects of the quaternization of the basic nitrogen of these 5-HT3 receptor ligands appear to be strictly structure-dependent suggesting that different binding modes are operative at 5-HT3 receptor binding site. The different effect of the quaternization of the basic nitrogen of structurally different ligands were rationalized in tern-is of the interaction with the receptor by means of the combined use of experimental techniques (X-ray diffraction and NMR studies) and computational simulation studies. (C) 2002 Elsevier Science Ltd. All rights reserved.

2002 - Synthesis, characterization, and molecular dynamics simulation of Na2O-CaO-SiO2-ZnO glasses [Articolo su rivista]
Lusvardi, Gigliola; Malavasi, Gianluca; Menabue, Ledi; Menziani, Maria Cristina
abstract

The glass of composition Na2O.CaO.2SiO(2) was modified upon addition of ZnO to obtain the series of glasses Na2O.CaO.2SiO(2).xZnO (x = 0.17, 0.34, 0.68), where x = 0.68 is the experimentally determined maximum zinc content that does not produce phase separation. The glasses were investigated by means of density and thermal measurements (,(glass-transition and crystallization temperatures); moreover, the phases separated upon crystallization were identified. The results of molecular dynamics (MD) simulations combined with the analysis of the crystal structure of the main phases separated (Na2Ca(SiO3)(2) and Na2ZnSiO4) provided insights into the structural role of zinc and its effect on the short- and medium-range order of the glass structures.

2002 - The Interactions of 5-HT3 Receptor with Arylpiperazine, Tropane, and Quinuclidine Ligands [Articolo su rivista]
A., Cappelli; M., Anzini; S., Vomero; L., Mennuni; F., Makovec; M., Hamon; DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina
abstract

The Interactions of 5-HT3 Receptor with Arylpiperazine, Tropane, and Quinuclidine Ligands

2002 - Theoretical descriptors for the quantitative rationalisation of plastocyanin mutant functional propertiess [Articolo su rivista]
DE RIENZO, Francesca; G., Grant; Menziani, Maria Cristina
abstract

A quantitative rationalisation of the effect of specific amino acids on the recognition process and redox characteristics of plastocyanin towards cytochrome f, as determined by point mutation experiments, has been attempted in this study. To achieve this goal we derived theoretical descriptors directly from the three-dimensional structure of the plastocyanin mutants, in the same manner as it is usually done for small drug-like molecules. The protein descriptors computed can be related to: (a) the electrostatic and dipole-dipole interactions, effective at long distance; (b) polar interactions whose features are encoded by charged partial surface area descriptors; (c) the propensity of the surface residues to form hydrogen bonding interactions; and (d) dispersion and repulsive interactions. Moreover, an estimation of mutation-dependent variation of redox potential observed has been obtained by electrostatic free energy calculations. The quantitative structure-activity relationship (QSAR) models offer structural interpretation of the point mutation experiment responses and can be of help in the design of new protein engineering experiments.

2001 - A computational model of the 5-HT3 receptor extracellular domain: search for ligand binding sites [Articolo su rivista]
Menziani, Maria Cristina; DE RIENZO, Francesca; A., Cappelli; M., Anzini; DE BENEDETTI, Pier Giuseppe
abstract

A three-dimensional model of the 5-HT3 receptor extracellular domain has been derived on the basis of the nicotinic acetylcholine receptor model recently published by Tsigelny et al. Maximum complementarity between the position and characteristics of mutated residues putatively involved in ligand interaction and the pharmacophoric elements derived by the indirect approach applied on several series of 5-HT3 ligands have been exploited to gain insights into the ligand binding modalities and to speculate on the mechanistic role of the structural components. The analysis of the three-dimensional model allows one to distinguish among amino acids that exert key roles in ligand interactions, subunit architecture, receptor assembly and receptor dynamics. For some of these, alternative roles with respect to the ones hypothesized by experimentalists are assigned. Different binding modalities for agonists and antagonists are highlighted, and residues which probably play a role in the transduction of binding into a change in conformational state of the receptor are suggested.

2001 - Control of metalloprotein reduction potential: The role of electrostatic and solvation effects probed on plastocyanin mutants [Articolo su rivista]
Battistuzzi, Gianantonio; Borsari, Marco; Loschi, Lodovica; Menziani, Maria Cristina; DE RIENZO, Francesca; Sola, Marco
abstract

The changes in the thermodynamics of Cu(II) reduction for spinach plastocyanin induced by point mutations altering the electrostatic potential in proximity of the copper center were determined through variable temperature direct electrochemistry experiments. In particular, the functionally important surface residues Leu12 and Gln88 were replaced with charged and polar residues, and Asn38 was substituted with Asp. The mutational variations of the reduction enthalpy and entropy were analyzed with a QSPR (quantitative structure-property relationships) approach, employing global and local theoretical descriptors defined and computed on the three-dimensional protein structure. The correlations found are informative on how electrostatic and solvation effects control the E degrees' values in this species through the combined effects on the reduction enthalpy and entropy. The changes in reduction enthalpy can be justified with electrostatic considerations. Most notably, enthalpy-entropy compensation phenomena play a significant role: the entropic effects due to the insertion of charged residues determine E degrees' changes that are invariably opposite to those induced by the concomitant enthalpic effects. Therefore, the resulting E degrees' changes are small or even opposite to those expected on simple electrostatic grounds. The mutational variation in the reduction entropy appears to be linked to the hydrogen bonding donor/acceptor character of the northern part of the protein, above the metal site, and to the electrostatic potential distribution around the copper site. Both properties influence the reduction-induced reorganization of the water molecules on the protein surface in the same region.

2001 - Electrostatic analysis and Brownian dynamics simulation of the association of plastocyanin and cytochrome F [Articolo su rivista]
DE RIENZO, Francesca; Rr, Gabdoulline; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Rc, Wade
abstract

The oxidation of cytochrome f by the soluble cupredoxin plastocyanin is a central reaction in the photosynthetic electron transfer chain of all oxygenic organisms. Here, two different computational approaches are used to gain new insights into the role of molecular recognition and protein-protein association processes in this redox reaction. First, a comparative analysis of the computed molecular electrostatic potentials of seven single and multiple point mutants of spinach plastocyanin (D42N, E43K, E43N, E43Q/D44N, E59K/E60Q, E59K/E60Q/E43N, Q88E) and the wt protein was carried out. The experimentally determined relative rates (k(2)) for the set of plastocyanin mutants are found to correlate well (r(2) = 0.90 - 0.97) with the computed measure of the similarity of the plastocyanin electrostatic potentials. Second, the effects on the plastocyanin/cytochrome f association rate of these mutations in the plastocyanin eastern site were evaluated by simulating the association of the wild type and mutant plastocyanins with cytochrome f by Brownian dynamics. Good agreement between the computed and experimental relative rates (k(2)) (r(2) = 0.89 - 0.92) was achieved for the plastocyanin mutants. The results obtained by applying both computational techniques provide support for the fundamental role of the acidic residues at the plastocyanin eastern site in the association with cytochrome f and in the overall electron-transfer process.

2001 - Enthalpic and entropic contributions to the mutational changes in the reduction potential of blue copper proteins [Abstract in Rivista]
Sola, Marco; Battistuzzi, Gianantonio; Borsari, Marco; G. W., Canters; E., de Waal; DE RIENZO, Francesca; Loschi, Lodovica; G., Warmerdam; Menziani, Maria Cristina
abstract

The changes in the reduction potential of Pseudomonas aeruginosa and Alcaligenes denitrificans azurins and spinachplastocyanin following point mutations and residue ionizations were factorized into the enthalpic and entropiccontributions through variable temperature direct electrochemistry experiments. The mutational variations of thereduction enthalpy and entropy were analyzed with a QSPR (Quantitative Structure-Property Relationships) approach,employing global and local theoretical descriptors defined and computed on the three dimensional protein structure.

2001 - Influence of small additions of Al2O3 on the properties of the Na2O center dot 3SiO(2) glass [Articolo su rivista]
Leonelli, Cristina; Lusvardi, Gigliola; Montorsi, Monia; Menziani, Maria Cristina; Menabue, Ledi; P., Mustarelli; L., Linati
abstract

Changes in the structural properties of sodium alumine-silicate glasses of general formula Na2O . xAl(2)O(3). (3-x)SiO2 were investigated as a function of Al2O3 concentration. The experimental evidences provided by density, elastic modulus, glass chemical resistance measures, Si-29 and Al-27 MAS NMR investigations were complemented by molecular dynamics simulations. While neither of the experimental techniques or computational investigation utilized in this study were able to furnish unequivocable responses for the rationalization of the measured properties of sodium alumine-silicate glasses, the synergistic application of experimental and computational techniques showed that the anomalies observed in bulk properties like density and elastic modulus find their origin in medium-range structural features.

2001 - Mapping and fitting the peripheral benzodiazepine receptor binding site by carboxamide derivatives. Comparison of different approaches to quantitative ligand-receptor interaction modeling [Articolo su rivista]
M., Anzini; A., Cappelli; S., Vomero; M., Seeber; Menziani, Maria Cristina; T., Langer; B., Hagen; C., Manzoni; Jj, Bourguignon
abstract

The synthetic-computational approach to the study of the binding site of peripheral benzodiazepine receptor (PBR) ligands related to 1-(2-chlorophenyl) -N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195, 1) within their receptor (Cappelli et al. J. Med. Chem. 1997, 40, 2910-2921) has been extended. A series of carboxamide derivatives endowed with differently substituted planar aromatic or heteroaromatic systems was designed with the aim of getting further information on the topological requisites of the carbonyl and aromatic moieties for interaction with the PER binding site. The synthesis of most of these compounds involves Weinreb amidation of the appropriate lactone as the key step. The most potent compound, among the newly synthesized ones, shows a nanomolar PER affinity similar to that shown by I and the presence of a basic N-ethyl-N-benzylaminomethyl group in S-position of the quinoline nucleus. Thus, it may be considered the first example of a new class of water soluble derivatives of 1. Several computational methods were used to furnish descriptors of the isolated ligands (indirect approaches) able to rationalize the variation in the binding affinity of the enlarged series of compounds. Sound QSAR models are obtained by size and shape descriptors (volume approach) which codify for the short-range contributions to Ligand-receptor interactions. Molecular descriptors which explicitly account; for the electrostatic contribution to the interaction (CoMFA, CoMSIA, and surface approaches) perform well, but they do not improve the quantitative models. Moreover, useful hints for the identification of the antagonist binding site in the three-dimensional modeling of the receptor (direct approach) were provided by the receptor hypothesis derived by the pharmacophoric approach. The ligand-receptor complexes obtained provided a detailed description of the modalities of the interaction and interesting suggestions for further experiments.

2001 - The 2-Methoxyethanol + 1,2-Dimethoxyethane + Water Ternary System: Static Relative Permittivity from -10 to 80 °C [Articolo su rivista]
Cocchi, Marina; DE BENEDETTI, Pier Giuseppe; Marchetti, Andrea; Menziani, Maria Cristina; Seeber, Renato; Tassi, Lorenzo; Ulrici, Alessandro
abstract

Static relative permittivities of the 2-methoxyethanol + 1,2-dimethoxyethane + water ternary solvent system were measured as a function of temperature (-10 less than or equal to t/degreesC less than or equal to 80) and of composition, over the whole molar fractions range 0 less than or equal to x(1), x(2), x(3) less than or equal to 1. The experimental values have been used to test some empirical relationships accounting for the dependence of epsilon on T. x(i), and on T, x(i) couples of values. A comparison between calculated and experimental data shows that these relationships can be profitably employed to predict E values in correspondence to experimental data gaps. The excess dielectric permittivity, epsilon (E), assumes, in the most cases, negative values for any compositions of the mixtures. while the values of the excess molar polarization, PE, are positive. The large values of the excess quantities are indicative of the strong specific interactions among similar, as well as different molecules in the mixtures. Discussion of the data in terms of Kirkwood correlation factor also gives information on the short-range intermolecular interactions among the components. suggesting the formation of two-components adducts rather than of than mure complex moieties involving all three molecular species.

2000 - Blue copper proteins: A comparative analysis of their molecular interaction properties [Articolo su rivista]
DE RIENZO, Francesca; Rr, Gabdoulline; Menziani, Maria Cristina; Rc, Wade
abstract

Blue copper proteins are type-I copper containing redox proteins whose role is to shuttle electrons from an electron donor to an electron acceptor in bacteria and plants. A large amount of experimental data is available on blue copper proteins; however, their functional characterization is hindered by the complexity of redox processes in biological systems. We describe here the application of a semiquantitative method based on a comparative analysis of molecular interaction fields to gain insights into the recognition properties of blue copper proteins. Molecular electrostatic and hydrophobic potentials were computed and compared for a set of 33 experimentally-determined structures of proteins from seven blue copper subfamilies, and the results were quantified by means of similarity indices. The analysis provides a classification of the blue copper proteins and shows that (1) comparison of the molecular electrostatic potentials provides useful information complementary to that highlighted by sequence analysis; (2) similarities in recognition properties can be detected for proteins belonging to different subfamilies, such as amicyanins and pseudoazurins, that may be isofunctional proteins; (3) dissimilarities in interaction properties, consistent with experimentally different binding specificities, may be observed between proteins belonging to the same subfamily, such as cyanobacterial and eukaryotic plastocyanins; (4) proteins with low sequence identity, such as azurins and pseudoazurins, can have sufficient similarity to bind to similar electron donors and accepters while having different binding specificity profiles.

2000 - Molecular dynamics simulations of alumina addition in sodium silicate glasses [Articolo su rivista]
Montorsi, Monia; Menziani, Maria Cristina; Leonelli, Cristina; Pellacani, Gian Carlo; A. N., Cormack
abstract

Molecular dynamics simulations of alumina containing silicate glasses have been performed in order to determine the influence of that ion on the final properties of the glasses. In particular, short- and mid-range structures were analyzed in terms of the distribution of non bridging oxygen, bridging oxygen, three bridging oxygen species in the glasses, along with the coordination number distribution (cn) and qn species distribution. The results support the hypothesis that the observed changes in the property of the glasses could be directly related to the coordination preferences of the Al ion.

2000 - The ad hoc supermolecule approach to receptor ligand design [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca; Menziani, Maria Cristina; Cocchi, Marina
abstract

Among the ligand design methods based on the theoretical QSAR paradigm, the simple ad hoc supermolecule approach is presented and applied to a highly non-congeneric set of a1-adrenergic receptor antagonists. The performance of the approach is satisfactory and highlights its (semi)quantitative ligand design potentiality.

2000 - The sodium-alumino silicate glasses: a molecular dynamic study [Articolo su rivista]
Montorsi, Monia; Menziani, Maria Cristina; Leonelli, Cristina; A. N., Cormack
abstract

Alumino silicate glasses (NAS) represent an interesting class of materials expecially in virtue of their final physical and chemical properties. Several models have been proposed to interpret the macroscopical behaviour of these ternary systems and in the last years computer simulations have been also largely used as useful complementary tools for the NAS glass structure characterisation.In this work we present the comparison between experimental and theoretical data obtained for a large range of compositions (R= Al/Na from 0.0064 up to 2) of alumina containing glasses.

2000 - Theoretical investigation of substrate specificity for cytochromes p450 IA2, p450 IID6 and p450 IIIA4 [Articolo su rivista]
DE RIENZO, Francesca; Fanelli, Francesca; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Three-dimensional models of the cytochromes P450 IA2, P450 IID6 and P450 IIIA4 were built by means of comparative modeling using the X-ray crystallographic structures of P450 CAM, P450 BM-3, P450 TERP and P450 ERYF as templates. The three cytochromes were analyzed both in their intrinsic structural features and in their interaction properties with fifty specific and non-specific substrates. Substrate/enzyme complexes were obtained by means of both automated rigid and flexible body docking. The comparative analysis of the three cytochromes and the selected substrates, in their free and bound forms, allowed for the building of semi-quantitative models of substrate specificity based on both molecular and intermolecular interaction descriptors. The results of this study provide new insights into the molecular determinants of substrate specificity for the three different eukaryotic P450 isozymes and constitute a useful tool for predicting the specificity of new compounds.

1999 - Novel potent and selective central 5-HT3 receptor ligands provided with different intrinsic efficacy. 2. Molecular basis of the intrinsic efficacy of arylpiperazine derivatives at the central 5-HT3 receptors [Articolo su rivista]
Cappelli, A; Anzini, M; Vomero, S; Canullo, L; Mennuni, L; Makovec, F; Doucet, E; Hamon, M; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Bruni, G; Romeo, Mr; Giorgi, G; Donati, A.
abstract

Novel 5-HT3 receptor ligands were designed and synthesized with the aim of obtaining deeper insight into the molecular basis of the intrinsic efficacy of arylpiperazines interacting with the central 5-HT3 receptor. The newly synthesized compounds and some previously published compounds belonging to the same class of heteroarylpiperazines were tested for their potential ability to displace [H-3]granisetron from rat cortical membranes. These 5-HT3 receptor binding studies revealed subnanomolar affinity in several of the compounds under study. The most active ligands were quipazine derivatives bearing a phenyl group in the 4-position and various oxygenated alkyl side chains in the 3-position of the quinoline nucleus. Qualitative and theoretical quantitative structure-affinity relationship studies were carried out, and the interaction model for the 5-HT3 ligands related to quipazine with their receptor, proposed in part 1 of the present work, was updated to incorporate the latest data. The potential 5-HT3 agonist/antagonist activity of 12 selected compounds was assessed in vitro on the 5-HT3 receptor-dependent [C-14]guanidinium uptake in NG 108-15 cells. Their intrinsic efficacy ranged from the 5-HT3 full agonist properties of compounds 7a and 8h,i to those of partial agonists 10a,d and antagonists 8b,d,e, and 9c,d,h,i. The comparison between these functional data and those relative to the previously described compounds suggested that in this class of 5-HT3 ligands the intrinsic efficacy is modulated in a rather subtle manner by the steric features of the heteroaryl moiety.

1999 - Relevance of theoretical molecular descriptors in quantitative structure-activity relationship analysis of alpha 1-adrenergic receptor antagonists [Articolo su rivista]
Menziani, Maria Cristina; Montorsi, Monia; DE BENEDETTI, Pier Giuseppe; Karelson, M.
abstract

A quantitative structure-activity relationship (QSAR) study of a wide series of structurally diverse alpha(1)-adrenergic receptor antagonists was performed using the CODESSA (Comprehensive Descriptors for Structural and Statistical Analysis) technique. Theoretical descriptors derived on a single structure and ad hoc defined size and shape descriptors were considered in the attempt of describing information relevant to receptor interaction. The relative effectiveness of these two classes of parameters in developing QSAR models for native (alpha(1A) and alpha(1B)) and cloned (alpha(1a), alpha(1b), and alpha(1d)) adrenergic receptor binding affinity, functional activity of vascular and lower urinary tract tissues, and in vitro and in vivo selectivity was evaluated. (C) 1999 Elsevier Science Ltd. All rights reserved.

1999 - Synthesis, pharmacological evaluation, and structure-activity relationship and quantitative structure-activity relationship studies on novel derivatives of 2,4-diamino-6,7-dimethoxyquinazoline alpha(1)-adrenoceptor antagonists [Articolo su rivista]
Leonardi, A; Motta, G; Boi, C; Testa, R; Poggesi, E; DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina
abstract

A new series of novel piperazine and non-piperazine derivatives of 2,4-diamino-6,7-dimethoxyquinazoline was synthesized and evaluated for binding affinity toward alpha(1)-adrenergic and other G-protein-coupled aminergic receptors. The alpha(1)-adrenoceptor (AR) subtype selectivity was also investigated for the most interesting compounds. Only compound 16 showed moderate selectivity toward the alpha(1b)-AR subtype. Selected compounds were tested in vivo in a dog model indicating activity on blood pressure and on the lower urinary tract. Compound 10 showed in vivo potency close to that of prazosin. Powerful interpretative and predictive theoretical QSAR models have been obtained. The theoretical descriptors employed in the rationalization of the alpha(1)-adrenergic binding affinity depict the key features for receptor binding which can be summarized in an electrostatic interaction between the protonated amine function and a primary nucleophilic site of the receptor, complemented by short-range attractive (polar and dispersive) and repulsive (steric) intermolecular interactions. Moreover, on predictive grounds, the ad hoc derived size and shape QSAR model developed in a previous paper (Rastelli, G.; et al. J. Mol. Struct. 1991, 251, 307-318) proved to be successful in predicting nanomolar alpha(1)-adrenergic binding affinity for compound 28.

1999 - Theoretical study on receptor-G protein recognition: new insights into the mechanism of the α1b-adrenergic receptor activation [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; A., Scheer; S., Cotecchia; DE BENEDETTI, Pier Giuseppe
abstract

Theoretical study on receptor/G protein recognition: new insights into the mechanism of the α1b-adrenergic receptor activation.

1999 - Theoretical study on the electrostatically driven step of receptor-G protein recognition [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; A., Scheer; Cotecchia, S.; DE BENEDETTI, Pier Giuseppe
abstract

Theoretical study on the electrostatically driven step of receptor-G protein recognition

1998 - Ab initio modeling and molecular dynamics simulation of the alpha 1b-adrenergic receptor activation [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; A., Scheer; S., Cotecchia; DE BENEDETTI, Pier Giuseppe
abstract

This work describes the ab initio procedure employed to build an activation model for the alpha(1b)-adrenergic receptor (alpha(1b)-AR). The first version of the model was progressively modified and complicated by means of a many-step iterative procedure characterized by the employment of experimental validations of the model in each upgrading step. a combined simulated (molecular dynamics) and experimental mutagenesis approach was used to determine the structural and dynamic features characterizing the inactive and active states of alpha(1b)-AR. The latest version of the model has been successfully challenged with respect to its ability to interpret and predict the functional properties of a large number of mutants. The iterative approach employed to describe alpha(1b)-AR activation in terms of molecular structure and dynamics allows further complications of the model to allow prediction and interpretation of an ever-increasing number of experimental data.

1998 - Computer modeling of size and shape descriptors of alpha 1-adrenergic receptor antagonists and quantitative structure-affinity/selectivity relationships [Articolo su rivista]
Montorsi, Monia; Menziani, Maria Cristina; Cocchi, Marina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Computational chemistry and molecular modeling procedures allow us to define and compute ad hoc size and shape descriptors on the different prototropic forms assumed by drugs in biotest solutions. Together with experimental data measured on a well-identified target receptor, these descriptors are essential elements for obtaining simple, consistent, comparable, and easily interpretable theoretical quantitative structure-activity relationship (QSAR) models based on the ligand similarity-target receptor complementarity paradigm. In this context, quantitative size and shape affinity/subtype selectivity relationships have been modeled for a large set of very heterogeneous alpha(1a)-, alpha(1b)-, and alpha(1d)-adrenergic receptor antagonists. The linear QSAR models generated have been validated by predicting both binding affinity and selectivity of a test set of noncongeneric antagonists. The satisfactory results obtained highlight both the simplicity and the versatility of the approach presented.

1998 - Novel potent and selective central 5-HT3 receptor ligands provided with different intrinsic efficacy. 1. Mapping the central 5-HT3 receptor binding site by arylpiperazine derivatives [Articolo su rivista]
Cappelli, A; Anzini, M; Vomero, S; Mennuni, L; Makovec, F; Doucet, E; Hamon, M; Bruni, G; Romeo, Mr; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Langer, T.
abstract

Synthesis and pharmacological evaluation of a series of condensed quinoline and pyridine derivatives bearing a N-methylpiperazine moiety attached to the 2-position of the quinoline or pyridine nucleus are described. 5-HT receptor binding studies revealed subnanomolar affinity for the 5-HT3 receptor subtype in some of the compounds under study. The most active compound (5b) displayed a K-i value about 1 order of magnitude higher than that of quipazine along with a higher selectivity. The potential 5-HT3 agonist/antagonist activity of four selected compounds was assessed in vitro on 5-HT3 receptor-dependent [C-14]guanidinium uptake in NG 108-15 cells. Compound 5j acted as a 5-HT3 agonist in this assay with an EC50 value close to that reported for quipazine, while 5b was a partial agonist with an EC50 value of about 0.25 nM, and compound 5c possessed antagonist properties with an IC50 value (approximate to 8 nM) in the same range as those of previously characterized 5-HT3 receptor antagonists. Qualitative and quantitative structure-affinity relationship studies carried out by making use of theoretical molecular descriptors allowed to elucidate the role of the main pharmacophoric components and to develop a model for the interaction of the 5-HT3 ligands related to quipazine with their receptor.

1998 - Theoretical descriptors in quantitative structure - Affinity and selectivity relationship study of potent N4-substituted arylpiperazine 5-HT1(Alpha) receptor antagonists [Articolo su rivista]
Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Karelson, M.
abstract

The ability of ad hoc defined size and shape descriptors and theoretical descriptors derived on a single structure to give poweful interpretative and predictive QSAR models has been compared and evaluated with respect to the quality of the pharmacological data available for a series of structurally diverse 5-HT1(A) receptor antagonists, displaying selectivity towards the alpha 1-adrenergic receptor. (C) 1998 Elsevier Science Ltd. All rights reserved.

1997 - Alpha 1-adrenoceptor subtype selectivity: Molecular modelling and theoretical quantitative structure-affinity relationships [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Fanelli, Francesca; Menziani, Maria Cristina; Cocchi, Marina; R., Testa; A., Leonardi
abstract

This study constitutes a preliminary rationalization, at the molecular level, of antagonist selectivity towards the three cloned alpha 1-adrenergic receptor (alpha 1-AR) subtypes. Molecular dynamics simulations allowed a structural/dynamics analysis of the seven alpha-helix-bundle models of the bovine alpha 1a-, hamster alpha 1b-, and rat alpha 1d-AR subtypes. The results showed that the transmembrane domains of these subtypes have different dynamic behaviours and different topographies of the binding sites, which are mainly constituted by conserved residues. In particular, the alpha 1a-AR binding site is more flexible and topographically different with respect to the other two subtypes. The results of the theoretical structural/dynamics analysis of the isolated receptors are consistent with the binding affinities of the 16 antagonists tested towards the three cloned alpha 1-AR subtypes. Moreover, the theoretical quantitative structure-affinity relationships obtained from the antagonist-receptor interaction models further corroborates the hypothesis that selectivity towards one preferential subtype is mainly modulated by receptor and/or ligand distortion energies. In other words, subtype selectivity seems to be mainly guided by the dynamic complementarity (induced fit) between ligand and receptor. On the basis of the quantitative models presented it is possible to predict both affinities and selectivities of putative alpha 1-AR ligands as well as to estimate the theoretical alpha 1-AR subtype affinities and selectivities of existing antagonists.

1997 - Conformational analysis and theoretical quantitative size and shape-affinity relationships of N-4-protonated N-1-arylpiperazine 5-HT1A serotoninergic ligands [Articolo su rivista]
Cocchi, Marina; Fanelli, Francesca; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Conformational analysis for 24 arylpiperazines in their neutral and N-4-protonated forms has been performed in the AM1 framework. Both these derivatives and eight reference compounds considered in this study are ligands of the 5-HT1A serotoninergic receptor. Quantum chemical reactivity indices, solvation free energies (AMSOL 5.0) and molecular modelling derived ad hoc size and shape descriptors have been computed and correlated with the literature 5-HT1A binding affinity data values. The quantitative size-shape affinity relationships obtained confirm the validity and versatility of the ad hoc descriptors employed. A different role has been postulated for the neutral and protonated forms of the arylpiperazines considered in the molecular recognition process of the 5-HT1A receptor binding site.

1997 - Mapping the peripheral benzodiazepine receptor binding site by conformationally restrained derivatives of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK11195) [Articolo su rivista]
Cappelli, A; Anzini, M; Vomero, S; Debenedetti, Pg; Menziani, Maria Cristina; Giorgi, G; Manzoni, C.
abstract

A synthetic-computational approach to the study of the binding site of peripheral benzodiazepine receptor (PER) ligands related to 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3- isoquinolinecarboxamide (PK11195, 1) within their receptor has been developed. A wide series of conformationally restrained derivatives of 1 has been designed with the aim of probing the PER binding site systematically. The synthesis of these compounds involves palladium-catalyzed coupling and amidation as the key steps. Twenty-nine rigid and semirigid derivatives of 1 were tested in binding studies using [H-3]-1, and most of these showed PER affinities in the nanomolar range. The essential role of the carbonyl moiety as a primary pharmacophoric element in the recognition by and the binding to PER has been confirmed, and the restricted range of the carbonyl orientations, which characterizes the most potent ligands, points to a specific hydrogen-bonding interaction, mainly directed by the geometrical factors, when the electronic ones are fulfilled. Moreover, the fundamental importance of the short-range dispersive interactions in the modulation of the binding affinity and, hence, in the stabilization of the ligand-receptor complex, emerged from the QSAR models reported.

1997 - Molecular dynamics of guest radicals in urea inclusion compounds [Articolo su rivista]
Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Segre, Ulderico; Brustolon, M.
abstract

Molecular dynamics simulations of several radical guests included in urea clathrates have been performed for a period of 1 ns. The starting conformations of the radicals have been obtained by AM1 quantum mechanical computations. The host matrix has been modelled as a single channel formed by 47 or 72 urea molecules, and different constraints imposed on the urea molecule positions have been tested to optimize the effect of the host confinement on the guest radicals. Two kinds of motion have been considered, the internal dynamics of the methylene group beta to the radical centre and the rotation of the guest inside the host channel. The simulation results have been compared with experimental data obtained by electron paramagnetic resonance spectroscopy. Good agreement is found for the internal motion when a finite harmonic constraint is imposed on the urea carbonyl. The correlation time for the molecular rotation is estimated to be longer than the simulation period. The slow reorientation process should be controlled by the concurrent rearrangement of the host matrix.

1997 - Theoretical investigation of IL-6 multiprotein receptor assembly [Articolo su rivista]
Menziani, Maria Cristina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Interleukin-6 (IL-6) is a multifunctional cytokine that regulates cell growth, differentiation, and cellular functions in many cell lineages, Recently, evidences for the formation of an active hexameric complex with an IL-6:IL-6R alpha:gp130 stoichiometry of 2:2:2 have been obtained by different experimental approaches, Analysis of the electrostatic potential complementarity between IL-6 and its receptors has been used, in this study to guide the assembly of homology-based 3D models of the components, The results strongly support a mechanism whereby the active cytokine (IL-6: IL-6R alpha) associates with the signal transducing gp130 protein, and the trimeric complex formed further dimerizes to form the hexameric species. Furthermore, computational simulations of the multiprotein complexes provide a rationalization of data from mutation experiments and highlight some key protein-protein interactions which have not yet been the subject of mutagenesis studies.

1996 - Computational simulations of stem-cell factor c-Kit receptor interaction [Articolo su rivista]
Menziani, Maria Cristina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Stem-cell factor (SCF) is a noncovalent homodimeric cytokine that exhibits profound biological function in the early stages of hematopoiesis by binding to a cell surface tyrosine kinase receptor that is encoded by the c-Kit proto-oncogene. The results obtained from a combined implementation of homology-based molecular modeling and computational simulations in the study of species-specific SCF/c-Kit interactions are reported. The structural models of the human and rat SCF Ligands are based on the close structural similarity to the cytokine M-CSF, whose C alpha structure has recently become available. The constant domains of the human Fc fragment are used as a template for the ligand binding domains of the c-Kit receptor. The factors responsible for the stabilization of the SCF quaternary structure and the molecular determinants for ligand recognition and ligand specificity have been identified by assessing the conformational, topographical, and dynamic features of the isolated ligands and of the ligand-receptor complexes.

1996 - Molecular structure and dynamics of some potent 5-HT3 receptor antagonists. Insight into the interaction with the receptor [Articolo su rivista]
Cappelli, A; Donati, A; Anzini, M; Vomero, S; DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Langer, T.
abstract

The molecular structure and the dynamic behaviour of some potent 5-HT3 antagonists structurally related to quipazine have been investigated by NMR spectroscopy and by computational methods in order to gain insight into the structure-activity relationships at a molecular level. The role of the different dynamic behaviour of these compounds in the binding to 5-HT3 receptors is discussed. A model of ligand-receptor interaction has been developed on the basis of molecular orbital calculations and on the reference ligands quipazine, ondansetron and LY278584. The interaction model proposed herein rationalizes the observed agonist-antagonist shift between quipazine and investigated compounds with the assumption of different but overlapping binding domains for antagonists and agonists at the 5-HT3 receptor. Copyright

1996 - Synthesis, biological evaluation, and quantitative receptor docking simulations of 2-[(acylamino)ethyl]-1,4-benzodiazepines as novel tifluadom-like ligands with high affinity and selectivity for kappa-opioid receptors [Articolo su rivista]
Cappelli, A; Anzini, M; Vomero, S; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Sbacchi, M; Clarke, Gd; Mennuni, L.
abstract

The synthesis and biological evaluation of a series of 2-substitued 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), the only benzodiazepine that acts simultaneously as a kappa-opioid agonist and a cholecystokinin-A (CCK-A) antagonist, are reported. The radioligand binding models used in these studies were [I-125(BH)-CCK-8 in rat pancreas (CCK-A), [H-3]-(MeNLE(28,31))-CCK-8 in guinea pig cerebral cortex (CCK-B), and [H-3]U-69593 (kappa(1)), [H-3]DAMGO (mu), and [H-3]DADLE (delta) in guinea pig brain. All the title compounds were devoid of significant affinity for both CCK-A and CCK-B receptors, while some of them bound with nanomolar affinity and high selectivity for kappa-opioid receptors. In particular, the 2-thienyl derivative 7a (X = H) with a K-i = 0.50 nM represents a clear improvement with respect to tifluadom, showing a comparable potency but higher selectivity. The application of computational simulations and linear regression analysis techniques to the complexes between guinea pig kappa (kappa(1))-receptor and the title compounds allowed the identification of the structural determinants for recognition and quantitative elucidation of the structure-affinity relationships in this class of receptors.

1996 - The Heuristic-Direct approach to Quantitative Structure-Activity Relationship Analysis of Ligand-G Protein Coupled Receptor Complexes [Capitolo/Saggio]
Menziani, Maria Cristina; Fanelli, Francesca; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe
abstract

The Heuristic-Direct approach to Quantitative Structure-Activity Relationship Analysis of Ligand-G Protein Coupled Receptor Complexes

1995 - Comparative molecular dynamics study of the seven-helix bundle arrangement of G-protein coupled receptors [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe
abstract

A comparative molecular dynamics study has been performed on the seven-helix bundle arrangement of seven G-protein coupled receptors (GPCRs). They are hamster alpha(1B)-, human alpha(2)-, beta(2)-adrenergic, human D-2-dopaminergic, human 5-HT1A-serotoninergic, human ml-muscarinic receptors and bovine rhodopsin. Starting from a rhodopsin-like input structure and a bacteriorhodopsin-like input structure, a similar arrangement of the averaged helix bundles was obtained. This may be due to the topography of some fundamental polar positions in both the input structures which is substantially the same and dictates, through the establishment of similar H-bonding networks, the helix-helix packing. By comparing the averaged structures and the packing interaction parameters obtained for the GPCRs considered with that of bacteriorhodopsin, we observe that the GPCRs share a similar packing arrangement of their transmembrane helix bundles which differs from that of bacteriorhodopsin. The results obtained from the quantitative and comparative molecular modelling of the GPCRs constitute an important preliminary step in a general understanding of both structure-function and structure activity-selectivity relationships in these proteins, at the molecular level.

1995 - Computer simulations of signal transduction mechanism in alpha 1B-adrenergic and m3-muscarinic receptors [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Molecular dynamics simulations of the hamster alpha(1B)-adrenergic and the rat m3-muscarinic seven-helix bundle receptor models have been carried out. The free, agonist-bound and antagonist-bound forms have been considered, Moreover, three mutant forms of the m3-muscarinic receptor (N507-->A, N507-->D and N507-->S) have also been simulated; among these, the N507-->S mutant shows a constitutive activity, A comparative structural/dynamics analysis has been performed to elucidate (i) the perturbations induced by the functionally different ligands upon binding to their target receptor, (ii) the features of the three single-point mutants with respect to the receptor wild type and (iii) the properties shared by the agonist-bound forms of the alpha(1B)-adrenergic receptor and the m3-muscarinic receptor and by the constitutively active mutant N507-->S. The consistency obtained between the structural rearrangement of the transmembrane seven-helix bundle models considered, and the experimental pharmacological efficacies of the ligands and of the mutants, constitute an important validation of the 3-D models obtained and allow the inference of the mechanism of ligand- or mutation-induced receptor activation at the molecular level.

1995 - Molecular dynamics simulations of m3-muscarinic receptor activation and QSAR analysis [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Molecular dynamics simulations of the rat m3-muscarinic seven-helix-bundle receptor models were performed on the free, agonist-bound and antagonist-bound forms. A comparative structural/dynamics analysis was performed in order to explain the perturbations induced by the functionally different ligands when binding to their target receptor. Theoretical quantitative structure-activity relationship models were developed; a good correlation was obtained between the interaction energies of the minimized average ligand-receptor complexes and the pharmacological affinities of the considered ligands. The consistency obtained between the structural rearrangement of the transmembrane seven-helix-bundle models considered and the experimental pharmacological efficacies and affinities of the ligands constitutes an important validation of the 3-D models proposed and allows the inference of the mechanism of ligand-induced or mutation-induced receptor activation at the molecular level.

1995 - Prototropic molecular forms and theoretical descriptors in QSAR analysis [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Cocchi, Marina; Fanelli, Francesca
abstract

Computational chemistry allows us to define and compute ad hoc theoretical reactivity and size-shape descriptors on the different prototropic forms assumed by drugs in pharmacological test solutions. These are essential elements for obtaining simple, consistent, comparable and easily interpretable theoretical QSAR models based on the ligand similarity-target complementarity paradigm. In this context, theoretical QSAR models have been obtained for 34 structurally and pharmacologically (antagonists, partial agonists and full agonists) heterogeneous M(1)-muscarinic ligands and the above concepts have been highlighted.

1995 - Quantitative structure-affinity/selectivity relationship analysis on three-dimensional models of the complexes between the ETA and ETB receptors and C-terminal endothelin hexapeptide antagonists [Articolo su rivista]
Menziani, Maria Cristina; Cocchi, Marina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

The application of molecular modelling and regression analysis techniques to the complexes between the ET(A) and ET(B) receptors and a series of C-terminal endothelin hexapeptide antagonists allowed the identification of the structural determinants for recognition and the quantitative elucidation of the receptor structure-affinity/selectivity relationships.

1995 - The Heuristic-Direct Approach to QSAR Analysis of Ligand-G-Protein Coupled Receptor Complexes [Capitolo/Saggio]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Fanelli, Francesca; Cocchi, Marina
abstract

Not available

1995 - Theoretical QSAR analysis on three dimensional models of the complexes between peptide and non-peptide antagonists with the ETA and ETB receptors [Capitolo/Saggio]
Menziani, Maria Cristina; Cocchi, Marina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Not available

1995 - Theoretical quantitative structure-activity relationship analysis of congeneric and non-congeneric α1-adrenoceptor antagonists: a chemometric study [Articolo su rivista]
Cocchi, Marina; Menziani, Maria Cristina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Molecular orbital calculations (AM1) and molecular modelling procedures (QUANTA/CHARMm) have been performed both on a congeneric (prazosin analogs) and on a non-congeneric series of alpha(1)-adrenergic antagonists. A large variety of theoretical molecular descriptors has been obtained and compared by principal component analysis (PCA). The generating optimal least squares estimations (GOLPE) procedure has been used to derive quantitative structure-activity relationships (QSARs). Good predictive QSAR models with a restricted pool of informative theoretical descriptors have been obtained. These results support the generality of the theoretical QSAR approach proposed; in fact both congeneric and non-congeneric molecular series were satisfactorily modeled. Moreover, the high and well-defined physical information content encoded in the theoretical descriptors considered allows the rationalization of the structural heterogeneity of the molecules examined as differences in the complementary intermolecular interactions of the studied ligands towards their common receptor.

1994 - The heuristic-direct approach to theoretical quantitative structure activity relationship analysis of α1- adrenoceptor ligands [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; Cocchi, Marina; A., Leonardi; DE BENEDETTI, Pier Giuseppe
abstract

The heuristic-direct quantitative structure-activity relationship approach has been applied to fifteen non-congeneric alpha1-adrenergic receptor (alpha1-AR) ligands interacting with the rat alpha1A/D-AR subtype. The good linear correlations, which have been obtained between calculated binding energies and the pharmacological affinities, allow one to predict the pharmacological affinity of new ligands. Moreover, according to the alpha1A/D-receptor model proposed, it has been possible to speculate on the amino acid residues which are mainly involved in the interaction with the ligands. This novel procedure consitutes a powerful tool for the design of new selective leads based on explicit intermolecular interactions and for suggesting site-directed mutagenesis studies, in order to give, iteractively, further support and improvement to the predictive and interpretative aspects of the model.

1994 - Theoretical Quantitative Structure-Activity Relationship Analysis on Three Dimensional Models of Ligand-m1 Muscarinic Receptor Complexes [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; A., Carotti; P. G., DE BENEDETTI
abstract

The heuristic-direct QSAR (quantitative structure-activity relationships) approach has been applied to a series of 34 muscarinic receptor ligands, including antagonists, weak partial agonists, partial agonists and full agonists, interacting with the human ml-muscarinic receptor subtype. The first step of this procedure consists of the computer-aided 3D-model building of the receptor. The second step involves docking simulations with selected ligands, maximizing the complementarity between ligand and receptor. In the third step, a detailed and extensive correlation analysis between the computed interaction energies, their components and the experimental pharmacological affinity and action is accomplished in order to evaluate the consistency of the QSAR model proposed and to provide a quantitative tool for comparisons among the different complexes considered. In this context, good linear correlations have been obtained between ad hoc theoretical intermolecular interaction descriptors and the pharmacological action, which allow one to classify quantitatively and predict the pharmacological action of new ligands. Finally, according to the ml-receptor model proposed, it has been possible to speculate on the amino acid residues which are mainly involved in the interaction with the ligands, and on the nature of the prevailing intermolecular interactions which are responsible for the different behaviour of antagonists, weak partial agonists, partial agonists and full agonists.

1994 - Theoretical quantitative size and shape activity and selectivity analyses of 5-HT1A serotonin and α1-adrenergic receptor ligands [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Cocchi, Marina; Menziani, Maria Cristina; Fanelli, Francesca
abstract

Quantum chemical reactivity indices and molecular modelling derived size and shape descriptors have been computed for 18 5-HT1A serotonin and alpha1-adrenergic receptor ligands. The quantitative size shape affinity selectivity relationships obtained support the general validity and versatility of the ad hoc size shape descriptors employed.

1993 - A MOLECULAR-DYNAMICS SIMULATION OF SEQUENCE-DIRECTED RECOGNITION PEPTIDES INTERACTING WITH BIGENDOTHELIN [Articolo su rivista]
Menziani, Maria Cristina; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe
abstract

Detailed insights into the mechanisms and forces responsible for the highly selective binding of three sequence-directed recognition peptides to bigendothelin are provided by the combined use of computer-aided model building techniques, molecular dynamics simulations and quantitative structure-activity analysis. The relevance of the analysis of the interactions between the peptides during the molecular dynamics simulation to peptide design is highlighted.

1993 - The heuristic-direct approach to quantitative structure-activity relationship analysis [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Fanelli, Francesca; Cocchi, Marina
abstract

The heuristic-direct approach to quantitative structure-activity relationship analysis

1993 - Theoretical quantitative structure-activity analysis and pharmacophore modelling of selective non congeneric α1a-adrenergic antagonists [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Cocchi, Marina; Menziani, Maria Cristina; Fanelli, Francesca
abstract

Quantitative structure-activity relationship (QSAR) analysis has been done by making use of theoretical molecular descriptors on 13 non-congeneric alpha1a-adrenoceptor antagonists. Linear QSAR models have been obtained between ad hoc molecular shape and size descriptors, defined with respect to a reference ''super-molecule'', and the antagonistic potency. These results, obtained for a highly non-congeneric set of molecules, increase the potential of this approach and the probability of designing new leads. Finally, the reference supermolecule represents the best three-dimensional complementarity towards the alpha1a-adrenoceptor subtype being modelled by superimposing the two most active and selective alpha1a-antagonists.

1993 - Theoretical quantitative structure-activity analysis of quinuclidine-based muscarinic cholinergic receptor ligands [Articolo su rivista]
Fanelli, Francesca; Menziani, Maria Cristina; Carotti, A; DE BENEDETTI, Pier Giuseppe
abstract

Quantitative structure-activity relationship analysis using ad hoc theoretical molecular descriptors was performed on a set of 22 quinuclidine-based muscarinic cholinergic receptor ligands. The results obtained support quantitatively a pharmacophoric interacting model which suggests that once the essential H-bonding interaction between the protonated quinuclidine nitrogen atom and a protophilic counterpart in the receptor is satisfied, different mechanisms of interaction become operative in order to differentiate between agonists, partial agonists and antagonists. In fact, the agonist behaviour is characterized by two H-bonding interactions, whereas mainly lipophilic interactions characterize the antagonistic behaviour. Finally, both the H-bond acceptor propensity of the agonists and lipophilic features of the antagonists are better accounted for by theoretical descriptors computed on the pharmacologically active protonated forms than by those computed on the neutral forms.

1993 - Three dimensional molecular modeling of the α1a-adrenoceptor. Direct 3D-QSAR modeling of selective antagonists [Capitolo/Saggio]
Fanelli, Francesca; Menziani, Maria Cristina; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe
abstract

three dimensional molecular modeling of the α1a-adrenoceptor. Direct 3D-QSAR modeling of selective antagonists

1992 - CORRELATION AND MULTIVARIATE ANALYSES OF SPECTROSCOPIC AND DIHYDROPTEROATE SYNTHASE INHIBITORY ACTIVITY DATA IN 4-AMINOARYL (MULTISUBSTITUTED ARYL) SULFONES [Articolo su rivista]
Cocchi, Marina; Iarossi, Dario; Frassineti, Chiara; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Nuclear magnetic resonance (H-1 and C-13), vibrational spectroscopy, and quantum chemical calculations (complete neglect of differential overlap/2 [CNDO/2]) have been used to investigate 20 biologically active title compounds, inhibitors of the dihydropteroate synthase. The data obtained have been comparatively analyzed by correlation and multivariate analyses. The results obtained show that also in the case of multisubstitution the electronic effect can be rationalized in terms of electronic charge perturbations which are transmitted from the multisubstituted aryl ring to the common biofunctional moiety 4-NH2-C6H4-SO2- trough the SO2 group, mainly via hyperconjugation. Good predictions of both spectroscopic and biological data are obtained by the partial least squares method using quantum chemical descriptors.

1992 - ELECTRONIC AND ELECTROSTATIC ASPECTS OF CARBONIC-ANHYDRASE INHIBITION BY SULFONAMIDES [Articolo su rivista]
Menziani, Maria Cristina; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe
abstract

A theoretical conformational analysis was performed within the AM1 framework for three benzenesulphonamide carbonic anhydrase inhibitors in their neutral and anionic forms. The theoretical reactivity and electrostatic indices obtained are compared with both the enzymic inhibitory potencies and the molecular orbital indices computed using a simple theoretical model of the carbonic anhydrase-sulphonamide complex. Finally, the inhibitory activities of the sulphonamides considered were correlated with the proton exchange and charge transfer propensities of the inhibitors. The role of the zinc ion in the inhibition mechanism seems to be mainly connected with the generation of an electrostatic field which favours the correct orientation of the SO2NH2 group and its anticipated deprotonation.

1992 - Molecular mechanics and quantum chemical qsar analysis in carbonic anhydrase-heterocyclic sulfonamide interactions [Articolo su rivista]
Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

The simulation of the interaction of carbonic anhydrase with 2-substituted 1,3,4-thiadiazole-5-sulfonamide derivatives has been carried out using molecular mechanics methods. The variation in inhibitory potency is very well accounted for by the calculated binding energies. In addition, certain theoretical molecular descriptors have proven to be suitable for modelling the interaction energy with specific residues in an extended environment of the active site metal Zn2+.

1992 - Molecular modeling and quantitaive structure activity relationship analysis using theoretical descriptors of 1,4-benzodioxan (WB-4101) related-compounds alpha-1-adrenergic antagonists [Articolo su rivista]
P., Venturelli; Menziani, Maria Cristina; Cocchi, Marina; Fanelli, Francesca; DE BENEDETTI, Pier Giuseppe
abstract

Quantitative structure-activity relationship analysis using theoretical molecular descriptors was done on a set of 30 1,4-benzodioxan (WB-4101) related compounds which are alpha1-adrenoceptor antagonists. The results obtained confirm quantitatively and in terms of reactivity and molecular shape descriptors, the results of previous qualitative structure-activity relationship studies. It was found that the protonated amine function plays a crucial role in the potency of the alpha1-adrenoceptor antagonism due to a charge reinforced hydrogen bond with a primary nucleophilic site of the receptor. Furthermore, the more electrophilic (high SN1LUMO values) the NH2+ group, the stronger the charge reinforced hydrogen bond with the receptor and the higher the blocking activity. It was also found that the three-dimensional shape of the antagonists is more similar to the shape of the most active reference molecule (WB-4101) the more potent antagonists are. Finally, the reactivity (E(LUMO)) and the ad hoc shape (V(D)(norm)) descriptors were used to obtain a bilinear equation which accounts for about 77% of the total variance in the pharmacological data.

1992 - THEORETICAL VERSUS EMPIRICAL MOLECULAR DESCRIPTORS IN MONOSUBSTITUTED BENZENES - A CHEMOMETRIC STUDY [Articolo su rivista]
Cocchi, Marina; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; Cruciani, G.
abstract

Quantum chemical methods and molecular modeling techniques allow the definition of a large number of molecular and local quantities characterizing the reactivity, the shape and the binding properties of a molecule as well as of molecular fragments and substituents. This study is focused on a systematic comparison of the theoretical molecular descriptors with both empirical (Hammett's and Taft's substituent constants, hydrophobic parameter, Verloop's steric parameters etc.) and experimental (substituent induced chemical shifts, molecular weight and molecular refractivity) descriptors. Fifty selected monosubstituted benzenes, including some charged substituents have been computed in the AM1 framework. Several theoretical descriptors have been extracted from the AM1 electronic wavefunction as well as molecular modeling techniques and they have been analyzed by principal component analysis and the partial least squares method. The results obtained are consistent with previous principal component studies concerning empirical descriptors, and highlight the interdependencies among theoretical and empirical molecular descriptors.

1991 - A THEORETICAL-STUDY OF THE STRUCTURE OF BIG ENDOTHELIN [Articolo su rivista]
Menziani, Maria Cristina; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe; Gilbert, Rg; Richards, Wg; Zamai, M; Caiolfa, Vr
abstract

Protein structure prediction and molecular dynamics simulations have been applied for elaborating the three dimensional structure of Big Endothelin (bigET). BigET is 38-amino acid peptide which is converted, by proteolytic cleavage, into Endothelin, the most potent and long lasting endothelium derived contracting factor identified up to date. The intervention of a specific, yet unknown, protease has been evoked. The determination of bigET tertiary structure will contribute to elucidate its proteolytic conversion. In-vitro experimental data on proteolytic fragmentation of bigET in the presence of known proteases and protein homogenates from endothelial cells have been considered for testing the proposed structure.

1991 - Conformational analysis, molecular modeling and quantitative structure-activity relationships studies of 2,4-diamino-6,7-dimethoxy-2-substituted quinazoline α1-adrenergic antagonists [Articolo su rivista]
Rastelli, Giulio; Fanelli, Francesca; Menziani, Maria Cristina; Cocchi, Marina; DE BENEDETTI, Pier Giuseppe
abstract

Conformational analysis (AM1), modeling of the molecular shape (QUANTA 3.0) and quantitative structure-activity relationship analysis were done on a set of 16 2,4-diamino-6,7-dimethoxy-2-substituted quinazoline alpha-1-adrenoceptor antagonists (prazosin analogs). The results obtained show that the 2-substituents of the analogs considered are quite flexible. Furthermore, they suggest that, once the electronic requirements of the common quinazoline moiety are satisfied, the binding affinities are modulated by the molecular shape of the quinazoline 2-substituent, through the optimization of both dispersive and steric interactions and the hydrophobic contribution.

1991 - Correlation and Multivariate Analyses of the Spectroscopic Data in 4'-Substituted 4-Nitro-difhenylsulfones [Articolo su rivista]
Cocchi, Marina; Iarossi, Dario; Frassineti, Chiara; Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Molecular descriptors such as quantum chemical indices, substituent constants, substituent chemical shifts values of monosubstituted benzenes, and different data analyses (linear regression, dual substituent parameters, and multivariate analysis) have been comparatively used in order to rationalize the electronic substituent effects and to predict C-13 nuclearmagnetic resonance (NMR) and vibrational spectroscopy (IR) data of the 14 title compounds. The results have been compared with those previously obtained for the biologically active 4'-substituted 4-aminodiphenylsulfones, inhibitors of the dihydropteroate synthase enzyme. Both the 4-nitro and the 4-amino sulfone series show similar transmission of the electronic substituent effects through the C(1)-SO2-C(1') moiety by a hyperconjugative mechanism. Good predictions of the spectroscopic data are obtained with the different models considered. However, the partial least-squares method and principal componenent analysis seem to be the most powerful predictive tools.

1991 - Direct and Indirect Theoretical QSAR Modelling in Sulfonamide Carbonic Anhydrase Inhibitors [Abstract in Atti di Convegno]
Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe
abstract

Direct and Indirect Theoretical QSAR Modelling in Sulfonamide Carbonic Anhydrase Inhibitors

1991 - MOLECULAR-ORBITAL STUDY OF THE NITROGEN BASICITY OF PRAZOSIN ANALOGS IN RELATION TO THEIR ALPHA-1-ADRENOCEPTOR BINDING-AFFINITY [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Rastelli, Giulio; Cocchi, Marina
abstract

AM1 theoretical molecular descriptors were computed for prazosin analogues (2-substituted 4-amino-6,7-dimethoxy derivatives of quinazoline, quinoline and isoquinoline) and and correlated with both their experimental acidity constants and alpha-1-adrenoceptor binding affinity data values. The results confirm the crucial role of the N1 protonated form of these derivatives for a selective and productive binding interaction with the alpha-1 adrenergic receptor.

1991 - QSAR Analysis Using Theoretical Molecular Descriptors in 2,4-Diamino-6,7-Dimethoxy Quinazoline 1-Adrenoceptor Antagonists. [Abstract in Atti di Convegno]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Rastelli, Giulio; Cocchi, Marina
abstract

QSAR Analysis,Theoretical Molecular Descriptors,Quinazoline,a1-Adrenoceptor Antagonists.

1991 - Theoretical conformational analysis, electronic structure and molecular modelling studies in dihydropteroate synthase in hibition by multisubstituted s [Articolo su rivista]
Sokolov, Yu. A.; Menziani, M. C.; Cocchi, M.; De Benedetti, P. G.
abstract

Theoretical conformational analysis (MNDO) has been performed for six selected 4-aminoaryl multisubstituted aryl sulphones (4'-NH2; 2',4'-Cl2; 2',4',6'-Cl3; 2'-OH, 4'-O-; 2'-Cl, 4'-O-; 2'-CH3,4'-O-) which are competitive inhibitors, with respect to the substrate 4-aminobenzoate, of the dihydropteroate synthase. These derivatives show multiple conformational energy minima mainly due to the torsional freedom of the sulphur-carbon bond (θ2) of the substituted aryl ring. The other sulphur-carbon torsional angle considered (θ1), lying on the biofunctional common moiety 4-NH2C6H4SO2, is quite rigid, with the aryl ring perpendicular to the C1-S-C1' plane (θ1=90 °). The most stable conformera for all the derivatives considered are θ1=90 ° and θ2=90 ° (butterfly conformation) and θ1=90 ° and θ2=60 °. The highly active derivatives are, in general, less flexible and the inhibitory potency of the six sulphones considered is rationalized in terms of the electronic features of their common moiety, which do not significantly change among the different conformera of the same derivative. Finally, a good matching was obtained by computer superposition between the substrate 4-NH2C6H4COO- and the biofunctional common moiety 4-NH2C6H4SO2 of the sulphones. © 1991.

1990 - QSAR analysis in 2,4-diamino-6,7-dimethoxy quinoline derivatives - α1-adrenoceptor antagonists - using the partial least squares (PLS) method and theoretical molecular descriptors [Articolo su rivista]
Cocchi, Marina; Menziani, Maria Cristina; Rastelli, Giulio; DE BENEDETTI, Pier Giuseppe
abstract

QSAR analysis in 2,4-diamino-6,7-dimethoxy quinoline derivatives - α1-adrenoceptor antagonists - using the partial least squares (PLS) method and theoretical molecular descriptors

1989 - A Theoretical Study of Conformation-Electronic Structure Relationships in Benzensulfonamide Inhibitors of Carbonic Anhydrase Enzyme. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Cocchi, Marina; Frassineti, Chiara
abstract

A Theoretical Study of Conformation-Electronic Structure Relationships in Benzensulfonamide Inhibitors of Carbonic Anhydrase Enzyme.

1989 - Comparative QSAR Analysis in Dihydropteroate Synthase Inhibition by Sulphones. Design of Some New Derivatives with Improved Petency. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Iarossi, Dario; Frassineti, Chiara; Menziani, Maria Cristina; Cocchi, Marina; Cennamo, Carlo
abstract

Comparative QSAR Analysis in Dihydropteroate Synthase Inhibition by Sulphones. Design of Some New Derivatives with Improved Petency.

1989 - Quantitative Structure-Activity Relationships in Dihydropteroate Synthase Inhibition by Multisubstituted Sulfones. Design and Synthesis of Some New Derivatives with Improved Potency. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Iarossi, Dario; Folli, Ugo; Frassineti, Chiara; Menziani, Maria Cristina; Cennamo, Carlo
abstract

Quantitative Structure-Activity Relationships in Dihydropteroate Synthase Inhibition by Multisubstituted Sulfones. Design and Synthesis of Some New Derivatives with Improved Potency.

1989 - Rational drug design: Binding free energy differences of carbonic anhydrase inhibitors [Articolo su rivista]
Menziani, Maria Cristina; C. A., Reynolds; W. G., Richards
abstract

The free energy perturbation method has been applied to calculate the binding energy of sulphonamide inhibitors to carbonic anhydrase; the agreement with experiment gives further evidence for the reliability of this method even for anionic inhibitors and supports its use in drug design.

1989 - The binding of benzenesulfonamides to carbonic anhydrase enzyme. A molecular mechanics study and quantitative structure-activity relationships [Articolo su rivista]
Menziani, Maria Cristina; DE BENEDETTI, Pier Giuseppe; F., Gago; W. G., Richards
abstract

Molecular mechanics methods have been applied to study the interaction between a series of 20 deprotonated benzenesulfonamides and the enzyme carbonic anhydrase. The different contributions to the binding energy have been evaluated and correlated with experimental inhibition data and molecular orbital indices of the sulfonamides in their bound conformation. The results suggest that the discrimination shown by the enzyme toward these inhibitors is dominated by the short-range van der Waals forces

1988 - Crystal and molecular structure of bis(2-amino-5-methyl-1,3,4-thiadiazole-N3)dibromomercury(II). A spectroscopic study and INDO calculations [Articolo su rivista]
Antolini, Luciano; Benedetti, Adriano; FABRETTI COSTANTINO, Antonio; Giusti, Aleardo; Menziani, Maria Cristina
abstract

The crystal structure of the compound Hg(amtz)2Br2(amtz= 2-amino-5-methyl-1,3,4-thiadiazole) was determined by X-ray crystallography. The compound crystallizes in the triclinic space group P1̄ with cell dimensions a = 9.133(2), b = 11.002(2), c = 8.404(2) Å, α = 102.65(2), β = 116.80(2), γ = 93.87(2)°, and Z = 2. The structure was solved by the heavy-atom method and refined by least-squares calculations. The structure consists of monomeric discrete molecules, in which the Hg atom is co-ordinated in a distorted tetrahedral geometry by two bromine ions and by two nitrogens of the 2-amino-5-methyl-1,3,4-thiadiazole ligands. Infrared bands are assigned, the 1H, 13C, and 199Hg n.m.r. spectra of the complex have been recorded, and INDO calculations are discussed.

1988 - Multinuclear NMR and Vibrational Spectroscopy Studies of the Substituent Effects in Benzensulfonamide Inhibitors of the Enzyme Carbonic Anhydrase. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Iarossi, Dario; Menziani, Maria Cristina; Frassineti, Chiara; Benedetti, Adriano
abstract

Multinuclear NMR and Vibrational Spectroscopy Studies of the Substituent Effects in Benzensulfonamide Inhibitors of the Enzyme Carbonic Anhydrase.

1987 - A Quantum Chemical QSAR Analysis of Carbonic Anhydrase Inhibition by Heterocyclic Sulfonamides. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Cocchi, Marina; Frassineti, Chiara
abstract

A Quantum Chemical QSAR Analysis of Carbonic Anhydrase Inhibition by Heterocyclic Sulfonamides.

1987 - Quantitative Structure-Activity Analysis in Dihydropteroate Synthase Inhibition by Sulphones. Comparison with Sulfanilamides. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Iarossi, Dario; Menziani, Maria Cristina; V., Caiolfa; Frassineti, Chiara; Cennamo, Carlo
abstract

Quantitative Structure-Activity Analysis in Dihydropteroate Synthase Inhibition by Sulphones. Comparison with Sulfanilamides.

1985 - A Quantum Chemical QSAR Study of Carbonic Anhydrase Inhibition by Sulfonamides. [Articolo su rivista]
DE BENEDETTI, Pier Giuseppe; Menziani, Maria Cristina; Frassineti, Chiara
abstract

A Quantum Chemical QSAR Study of Carbonic Anhydrase Inhibition by Sulfonamides.

Università degli studi di Modena e Reggio Emilia

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