Alessandra Villa

Bio: Alessandra Villa is an academic researcher from Karolinska Institutet. The author has contributed to research in topics: Fusion protein & Antibody. The author has an hindex of 26, co-authored 83 publications receiving 5169 citations. Previous affiliations of Alessandra Villa include University of Milan & National Autonomous University of Mexico.

A biomolecular force field based on the free enthalpy of hydration and solvation: the GROMOS force-field parameter sets 53A5 and 53A6.

Abstract: Successive parameterizations of the GROMOS force field have been used successfully to simulate biomolecular systems over a long period of time. The continuing expansion of computational power with time makes it possible to compute ever more properties for an increasing variety of molecular systems with greater precision. This has led to recurrent parameterizations of the GROMOS force field all aimed at achieving better agreement with experimental data. Here we report the results of the latest, extensive reparameterization of the GROMOS force field. In contrast to the parameterization of other biomolecular force fields, this parameterization of the GROMOS force field is based primarily on reproducing the free enthalpies of hydration and apolar solvation for a range of compounds. This approach was chosen because the relative free enthalpy of solvation between polar and apolar environments is a key property in many biomolecular processes of interest, such as protein folding, biomolecular association, membrane formation, and transport over membranes. The newest parameter sets, 53A5 and 53A6, were optimized by first fitting to reproduce the thermodynamic properties of pure liquids of a range of small polar molecules and the solvation free enthalpies of amino acid analogs in cyclohexane (53A5). The partial charges were then adjusted to reproduce the hydration free enthalpies in water (53A6). Both parameter sets are fully documented, and the differences between these and previous parameter sets are discussed.

Magnesium Ion–Water Coordination and Exchange in Biomolecular Simulations

Abstract: Magnesium ions have an important role in the structure and folding mechanism of ribonucleic acid systems. To properly simulate these biophysical processes, the applied molecular models should reproduce, among other things, the kinetic properties of the ions in water solution. Here, we have studied the kinetics of the binding of magnesium ions with water molecules and nucleic acid systems using molecular dynamics simulation in detail. We have validated the parameters used in biomolecular force fields, such as AMBER and CHARMM, for Mg2+ ions and also for the biologically relevant ions Na+, K+, and Ca2+ together with three different water models (TIP3P, SPC/E, and TIP5P). The results show that Mg2+ ions have a slower exchange rate than Na+, K+, and Ca2+ in agreement with the experimental trend, but the simulated value underestimates the experimentally observed Mg2+–water exchange rate by several orders of magnitude, irrespective of the force field and water model. A new set of parameters for Mg2+ was develop...

Calculation of the free energy of solvation for neutral analogs of amino acid side chains.

Abstract: The ability of the GROMOS96 force field to reproduce partition constants between water and two less polar solvents (cyclohexane and chloroform) for analogs of 18 of the 20 naturally occurring amino acids has been investigated. The estimations of the solvation free energies in water, in cyclohexane solution, and chloroform solution are based on thermodynamic integration free energy calculations using molecular dynamics simulations. The calculations show that while the force field reproduces the experimental solvation free energies of nonpolar analogs with reasonable accuracy the solvation free energies of polar analogs in water are systematically overestimated (too positive). The dependence of the calculated free energies on the atomic partial charges was also studied. (C) 2002 Wiley Periodicals, Inc.

Understanding binding affinity: a combined isothermal titration calorimetry/molecular dynamics study of the binding of a series of hydrophobically modified benzamidinium chloride inhibitors to trypsin.

Abstract: The binding of a series of p-alkylbenzamidinium chloride inhibitors to the serine proteinase trypsin over a range of temperatures has been studied using isothermal titration (micro)calorimetry and molecular dynamics simulation techniques. The inhibitors have small structural variations at the para position of the benzamidinium ion. They show small differences in relative binding affinity but large compensating differences in enthalpy and entropy. Binding affinity decreases with increased branching at the first carbon but increases with increasing the length of a linear alkyl substituent, suggesting that steric hindrance and hydrophobic interactions play dominant roles in binding. Structural analysis showed that the backbone of the enzyme was unaffected by the change of the para substituent. In addition, binding does not correlate strongly with octanol/water partition data. To further characterize this system, the change in the heat capacity on binding, the change in solvent-accessible surface area on binding, the effect of inhibitor binding on the hydration of the active site, the pK(a) of His57, and interactions within the catalytic triad have been investigated. Although the changes in inhibitor structure are small, it is demonstrated that simple concepts such as steric hindrance, hydrophobicity, and buried surface area are insufficient to explain the binding data. Other factors, such as access to the binding site and the cost of dehydration of the active site, are of equal or greater importance.

On the characterization of host-guest complexes: Surface tension, calorimetry, and molecular dynamics, of cyclodextrins with a non-ionic surfactant

Abstract: Three host-guest systems have been characterized using surface tension (sigma), calorimetry, and molecular dynamics simulations (MD). The hosts were three native cyclodextrins (CD) and the guest the non-ionic carbohydrate surfactant octyl-beta-d-glucopyranoside. It is shown that, for any host-guest system, a rough screening of the most probable complex stoichiometries can be obtained in a model free form, using only calorimetric data. The sigma data were analyzed using a model that includes a newly proposed adsorption isotherm. The equilibrium constants for several stoichiometries were simultaneously obtained through fitting the sigma data. For alpha- and beta-CD, the predominant species is 1:1 and to a lesser extent 2:1, disregarding the existence of the 1:2. For gamma-CD, the 1:2 species dominates, the other two being also present. In an attempt to confirm these results, 10 ns MD simulations for each CD were performed using seven different starting conformations. The MD stable conformations agree with the results found from the experimental data. In one case, the spontaneous dissociation-formation of a complex was observed. Analysis of the trajectories indicates that hydrophobic interactions are primarily responsible for the formation and stability of the inclusion complexes. For the 2:1 species, intermolecular H-bonds between CD molecules result in a tight packed structure where their original truncated cone shape is lost in favor of a cylindrical geometry. Together, the results clearly demonstrate that the often used assumption of considering only a 1:1 species is inappropriate.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

GROMACS: Fast, flexible, and free

Abstract: This article describes the software suite GROMACS (Groningen MAchine for Chemical Simulation) that was developed at the University of Groningen, The Netherlands, in the early 1990s. The software, written in ANSI C, originates from a parallel hardware project, and is well suited for parallelization on processor clusters. By careful optimization of neighbor searching and of inner loop performance, GROMACS is a very fast program for molecular dynamics simulation. It does not have a force field of its own, but is compatible with GROMOS, OPLS, AMBER, and ENCAD force fields. In addition, it can handle polarizable shell models and flexible constraints. The program is versatile, as force routines can be added by the user, tabulated functions can be specified, and analyses can be easily customized. Nonequilibrium dynamics and free energy determinations are incorporated. Interfaces with popular quantum-chemical packages (MOPAC, GAMES-UK, GAUSSIAN) are provided to perform mixed MM/QM simulations. The package includes about 100 utility and analysis programs. GROMACS is in the public domain and distributed (with source code and documentation) under the GNU General Public License. It is maintained by a group of developers from the Universities of Groningen, Uppsala, and Stockholm, and the Max Planck Institute for Polymer Research in Mainz. Its Web site is http://www.gromacs.org.

The MARTINI force field : Coarse grained model for biomolecular simulations

Abstract: We present an improved and extended version of our coarse grained lipid model. The new version, coined the MARTINI force field, is parametrized in a systematic way, based on the reproduction of partitioning free energies between polar and apolar phases of a large number of chemical compounds. To reproduce the free energies of these chemical building blocks, the number of possible interaction levels of the coarse-grained sites has increased compared to those of the previous model. Application of the new model to lipid bilayers shows an improved behavior in terms of the stress profile across the bilayer and the tendency to form pores. An extension of the force field now also allows the simulation of planar (ring) compounds, including sterols. Application to a bilayer/cholesterol system at various concentrations shows the typical cholesterol condensation effect similar to that observed in all atom representations.

Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ(1) and χ(2) dihedral angles.

Abstract: While the quality of the current CHARMM22/CMAP additive force field for proteins has been demonstrated in a large number of applications, limitations in the model with respect to the equilibrium between the sampling of helical and extended conformations in folding simulations have been noted. To overcome this, as well as make other improvements in the model, we present a combination of refinements that should result in enhanced accuracy in simulations of proteins. The common (non Gly, Pro) backbone CMAP potential has been refined against experimental solution NMR data for weakly structured peptides, resulting in a rebalancing of the energies of the α-helix and extended regions of the Ramachandran map, correcting the α-helical bias of CHARMM22/CMAP. The Gly and Pro CMAPs have been refitted to more accurate quantum-mechanical energy surfaces. Side-chain torsion parameters have been optimized by fitting to backbone-dependent quantum-mechanical energy surfaces, followed by additional empirical optimization targeting NMR scalar couplings for unfolded proteins. A comprehensive validation of the revised force field was then performed against data not used to guide parametrization: (i) comparison of simulations of eight proteins in their crystal environments with crystal structures; (ii) comparison with backbone scalar couplings for weakly structured peptides; (iii) comparison with NMR residual dipolar couplings and scalar couplings for both backbone and side-chains in folded proteins; (iv) equilibrium folding of mini-proteins. The results indicate that the revised CHARMM 36 parameters represent an improved model for the modeling and simulation studies of proteins, including studies of protein folding, assembly and functionally relevant conformational changes.

A biomolecular force field based on the free enthalpy of hydration and solvation: the GROMOS force-field parameter sets 53A5 and 53A6.

Abstract: Successive parameterizations of the GROMOS force field have been used successfully to simulate biomolecular systems over a long period of time. The continuing expansion of computational power with time makes it possible to compute ever more properties for an increasing variety of molecular systems with greater precision. This has led to recurrent parameterizations of the GROMOS force field all aimed at achieving better agreement with experimental data. Here we report the results of the latest, extensive reparameterization of the GROMOS force field. In contrast to the parameterization of other biomolecular force fields, this parameterization of the GROMOS force field is based primarily on reproducing the free enthalpies of hydration and apolar solvation for a range of compounds. This approach was chosen because the relative free enthalpy of solvation between polar and apolar environments is a key property in many biomolecular processes of interest, such as protein folding, biomolecular association, membrane formation, and transport over membranes. The newest parameter sets, 53A5 and 53A6, were optimized by first fitting to reproduce the thermodynamic properties of pure liquids of a range of small polar molecules and the solvation free enthalpies of amino acid analogs in cyclohexane (53A5). The partial charges were then adjusted to reproduce the hydration free enthalpies in water (53A6). Both parameter sets are fully documented, and the differences between these and previous parameter sets are discussed.