Wilfred F. van Gunsteren

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

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.

A generalized reaction field method for molecular dynamics simulations

Molecular dynamics simulations of ionic systems require the inclusion of long‐range electrostatic forces. We propose an expression for the long‐range electrostatic forces based on an analytical solution of the Poisson–Boltzmann equation outside a spherical cutoff, which can easily be implemented in molecular simulation programs. An analytical solution of the linearized Poisson–Boltzmann (PB) equation valid in a spherical region is obtained. From this general solution special expressions are derived for evaluating the electrostatic potential and its derivative at the origin of the sphere. These expressions have been implemented for molecular dynamics (MD) simulations, such that the surface of the cutoff sphere around a charged particle is identified with the spherical boundary of the Poisson–Boltzmann problem. The analytical solution of the Poisson–Boltzmann equation is valid for the cutoff sphere and can be used for calculating the reaction field forces on the central charge, assuming a uniform continuum ...

Peptide folding: When simulation meets experiment

Mol. dynamics simulation studies on the folding of beta-peptides H-beta3-HVal-beta3-HAla-beta3-HLeu-(S,S)-beta3-HAla(alphaMe)-beta3-HVal-beta3-HAla-beta3-HLeu-OH and H-beta2-HVal-beta3-HAla-beta2-HLeu-beta3-HVal-beta2-HAla-beta3-HLeu-OH were carried out. Despite the small differences in sequence between the two peptides studied, the simulations correctly predict a left-handed 31-helical fold for the beta-heptapeptide and a right-handed helical fold for the beta-hexapeptide.

An Improved GROMOS96 Force Field for Aliphatic Hydrocarbons in the Condensed Phase

Over the past 4 years the GROMOS96 force field has been successfully used in biomolecular simulations, for example in peptide folding studies and detailed protein investigations, but no applications to lipid systems have been published yet. Here we provide a detailed investigation of aliphatic liquid systems. For liquids of larger aliphatic chains, n‐heptane and longer, the standard GROMOS96 parameter sets 43A1 and 43A2 yield a too low pressure at the experimental density. Therefore, a reparametrization of the GROMOS96 force field regarding aliphatic carbons was initiated. The new force field parameter set 45A3 shows considerable improvements for n‐alkanes, cyclo‐, iso‐, and neoalkanes and other branched aliphatics. Liquid densities and heat of vaporization are reproduced for almost all of these molecules. Excellent agreement is found with experiment for the free energy of hydration for alkanes. The GROMOS96 45A3 parameter set should, therefore, be suitable for application to lipid aggregates such as membranes and micelles, for mixed systems of aliphatics with or without water, for polymers, and other apolar systems that may interact with different biomolecules.

Avoiding singularities and numerical instabilities in free energy calculations based on molecular simulations

A simple, general and numerically stable approach for avoiding the singularities which generally occur when atoms or interaction sites are created or annihilated in free energy calculations based on computer simulations is presented. The origin of such singularities and numerical instabilities occurring in Monte Carlo or molecular dynamics simulations is discussed, as is the limited accuracy of the techniques currently used to avoid such difficulties.

Definition and testing of the GROMOS force-field versions 54A7 and 54B7.

New parameter sets of the GROMOS biomolecular force field, 54A7 and 54B7, are introduced. These parameter sets summarise some previously published force field modifications: The 53A6 helical propensities are corrected through new φ/ψ torsional angle terms and a modification of the N–H, C=O repulsion, a new atom type for a charged −CH3 in the choline moiety is added, the Na+ and Cl− ions are modified to reproduce the free energy of hydration, and additional improper torsional angle types for free energy calculations involving a chirality change are introduced. The new helical propensity modification is tested using the benchmark proteins hen egg-white lysozyme, fox1 RNA binding domain, chorismate mutase and the GCN4-p1 peptide. The stability of the proteins is improved in comparison with the 53A6 force field, and good agreement with a range of primary experimental data is obtained.

The GROMOS software for biomolecular simulation: GROMOS05

We present the latest version of the Groningen Molecular Simulation program package, GROMOS05. It has been developed for the dynamical modelling of (bio)molecules using the methods of molecular dynamics, stochastic dynamics, and energy minimization. An overview of GROMOS05 is given, highlighting features not present in the last major release, GROMOS96. The organization of the program package is outlined and the included analysis package GROMOS++ is described. Finally, some applications illustrating the various available functionalities are presented.

A fast SHAKE algorithm to solve distance constraint equations for small molecules in molecular dynamics simulations

A common method for the application of distance constraints in molecular simulations employing Cartesian coordinates is the SHAKE procedure for determining the Lagrange multipliers regarding the constraints. This method relies on the linearization and decoupling of the equations governing the atomic coordinate resetting corresponding to each constraint in a molecule, and is thus iterative. In the present study, we consider an alternative method, M‐SHAKE, which solves the coupled equations simultaneously by matrix inversion. The performances of the two methods are compared in simulations of the pure solvents water, dimethyl sulfoxide, and chloroform. It is concluded that M‐SHAKE is significantly faster than SHAKE when either (1) the molecules contain few distance constraints (solvent), or (2) when a high level of accuracy is required in the application of the constraints.

Local elevation: A method for improving the searching properties of molecular dynamics simulation

SummaryThe concept of memory has been introduced into a molecular dynamics algorithm. This was done so as to persuade a molecular system to visit new areas of conformational space rather than be confined to a small number of low-energy regions. The method is demonstrated on a simple model system and the 11-residue cyclic peptide cyclosporin A. For comparison, calculations were also performed using simulated temperature annealing and a potential energy annealing scheme. Although the method can only be applied to systems with a small number of degrees of freedom, it offers the chance to generate a multitude of different low-energy structures, where other methods only give a single one or few. This is clearly important in problems such as drug design, where one is interested in the conformational spread of a system.

Validation of the 53A6 GROMOS force field

The quality of biomolecular dynamics simulations relies critically on the force field that is used to describe the interactions between particles in the system. Force fields, which are generally parameterized using experimental data on small molecules, can only prove themselves in realistic simulations of relevant biomolecular systems. In this work, we begin the validation of the new 53A6 GROMOS parameter set by examining three test cases. Simulations of the well-studied 129 residue protein hen egg-white lysozyme, of the DNA dodecamer d(CGCGAATTCGCG)2, and a proteinogenic β3-dodecapeptide were performed and analysed. It was found that the new parameter set performs as well as the previous parameter sets in terms of protein (45A3) and DNA (45A4) stability and that it is better at describing the folding–unfolding balance of the peptide. The latter is a property that is directly associated with the free enthalpy of hydration, to which the 53A6 parameter set was parameterized.