Alan E. Mark

GROMACS: Fast, flexible, and free

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.

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.

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.

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.

An Automated Force Field Topology Builder (ATB) and Repository: Version 1.0

The Automated force field Topology Builder (ATB, http://compbio.biosci.uq.edu.au/atb ) is a Web-accessible server that can provide topologies and parameters for a wide range of molecules appropriate for use in molecular simulations, computational drug design, and X-ray refinement. The ATB has three primary functions: (1) to act as a repository for molecules that have been parametrized as part of the GROMOS family of force fields, (2) to act as a repository for pre-equilibrated systems for use as starting configurations in molecular dynamics simulations (solvent mixtures, lipid systems pre-equilibrated to adopt a specific phase, etc.), and (3) to generate force field descriptions of novel molecules compatible with the GROMOS family of force fields in a variety of formats (GROMOS, GROMACS, and CNS). Force field descriptions of novel molecules are derived using a multistep process in which results from quantum mechanical (QM) calculations are combined with a knowledge-based approach to ensure compatibility (as far as possible) with a specific parameter set of the GROMOS force field. The ATB has several unique features: (1) It requires that the user stipulate the protonation and tautomeric states of the molecule. (2) The symmetry of the molecule is analyzed to ensure that equivalent atoms are assigned identical parameters. (3) Charge groups are assigned automatically. (4) Where the assignment of a given parameter is ambiguous, a range of possible alternatives is provided. The ATB also provides several validation tools to assist the user to assess the degree to which the topology generated may be appropriate for a given task. In addition to detailing the steps involved in generating a force field topology compatible with a specific GROMOS parameter set (GROMOS 53A6), the challenges involved in the automatic generation of force field parameters for atomic simulations in general are discussed.

Mechanism by which 2,2,2-trifluoroethanol/water mixtures stabilize secondary-structure formation in peptides: A molecular dynamics study

Molecular dynamics simulation techniques have been used to investigate the effect of 2,2,2-trifluoroethanol (TFE) as a cosolvent on the stability of three different secondary structure-forming peptides: the α-helix from Melittin, the three-stranded β-sheet peptide Betanova, and the β-hairpin 41–56 from the B1 domain of protein G. The peptides were studied in pure water and 30% (vol/vol) TFE/water mixtures at 300 K. The simulations suggest that the stabilizing effect of TFE is induced by the preferential aggregation of TFE molecules around the peptides. This coating displaces water, thereby removing alternative hydrogen-bonding partners and providing a low dielectric environment that favors the formation of intrapeptide hydrogen bonds. Because TFE interacts only weakly with nonpolar residues, hydrophobic interactions within the peptides are not disrupted. As a consequence, TFE promotes stability rather than inducing denaturation.

Toroidal pores formed by antimicrobial peptides show significant disorder

A large variety of antimicrobial peptides have been shown to act, at least in vitro, by poration of the lipid membrane. The nanometre size of these pores, however, complicates their structural characterization by experimental techniques. Here we use molecular dynamics simulations, to study the interaction of a specific class of antimicrobial peptides, melittin, with a dipalmitoylphosphatidylcholine bilayer in atomic detail. We show that transmembrane pores spontaneously form above a critical peptide to lipid ratio. The lipid molecules bend inwards to form a toroidally shaped pore but with only one or two peptides lining the pore. This is in strong contrast to the traditional models of toroidal pores in which the peptides are assumed to adopt a transmembrane orientation. We find that peptide aggregation, either prior or after binding to the membrane surface, is a prerequisite to pore formation. The presence of a stable helical secondary structure of the peptide, however is not. Furthermore, results obtained with modified peptides point to the importance of electrostatic interactions in the poration process. Removing the charges of the basic amino-acid residues of melittin prevents pore formation. It was also found that in the absence of counter ions pores not only form more rapidly but lead to membrane rupture. The rupture process occurs via a novel recursive poration pathway, which we coin the Droste mechanism.

Folding-unfolding thermodynamics of a beta-heptapeptide from equilibrium simulations.

The thermodynamics of folding and unfolding of a β‐heptapeptide in methanol solution has been studied at four different temperatures, 298 K, 340 K, 350 K, and 360 K, by molecular dynamics simulation. At each of these temperatures, the 50‐ns simulations were sufficient to generate an equilibrium distribution between a relatively small number of conformations (∼102), showing that, even above the melting temperature (∼340 K), the peptide does not randomly sample conformational space. The free energy of folding and the free energy difference between pairs of conformations have been calculated from their relative populations. The experimentally determined folded conformation at 298 K, a left‐handed 31‐helix, is at each of the four temperatures the predominant conformation, with its probability and average lifetime decreasing with increasing temperature. The most common intermediates of folding and unfolding are also the same at the four temperatures. Paths and rates of interconversion between different conformations have been determined. It has been found that folding can occur through multiple pathways, not necessarily downhill in free energy, although the final step involves a reduced number of intermediates. Proteins 1999;34:269–280.

Parametrization of aliphatic CHn united atoms of GROMOS96 force field

The derivation of the van der Waals parameters for the aliphatic CHn united atoms of the GROMOS96 force field is presented. The parameters have been adjusted to reproduce the experimental enthalpies of vaporization and vapor pressures or densities of a set of nine alkanes in the liquid state at 298 K (or at the boiling point in the case of methane), using a cutoff radius for the van der Waals interactions of 1.6 nm. Force fields to be used in molecular simulations are bound to the conditions chosen for their parametrization, for example, the temperature, the densities of the systems included in the calibration set, or the cutoff radius used for the nonbonded interactions. Van der Waals parameters for the CHn united atoms of earlier GROMOS force fields were developed using a cutoff radius of 0.8 nm for the van der Waals interactions. Because the van der Waals interaction energy between aliphatic groups separated by distances between 0.8 and 1.4 nm is not negligible at liquid densities, the use of these parameters in combination with longer cutoffs leads to an overestimation of the attractive van der Waals interaction energy. The relevance of this excess attraction depends on the size of the groups that are interacting, as well as on their local densities. Free energies of hydration have been calculated for five alkanes. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 535–547, 1998