Mika A. Kastenholz

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 consistent potential energy parameter set for lipids: dipalmitoylphosphatidylcholine as a benchmark of the GROMOS96 45A3 force field

The performance of the GROMOS96 parameter set 45A3 developed for aliphatic alkanes is tested on a bilayer of dipalmitoylphosphatidylcholine (DPPC) in water in the liquid-crystalline Lα phase. Variants of the force-field parameter set as well as different sets of simulation conditions or simulation parameter sets are evaluated. In the case of the force-field parameters, the van der Waals constants for the non-bonded interaction of the ester carbonyl carbon and the partial charges and charge group definition of the phosphatidylcholine head group are examined. On the methodological side, different cut-off distances for the non-bonded interactions, use of a reaction-field force due to long-range electrostatic interactions, the frequency of removal of the centre of mass motion and the strength of the coupling of the pressure of the system to the pressure bath are tested. The area per lipid, as a measure of structure, the order parameters of the chain carbons, as a measure of membrane fluidity, and the translational diffusion of the lipids in the plane of the bilayer are calculated and compared with experimental values. An optimal set of simulation parameters for which the GROMOS96 parameter set 45A3 yields a head group area, chain order parameters and a lateral diffusion coefficient in accordance with the experimental data is listed.

An improved nucleic acid parameter set for the GROMOS force field

Over the past decades, the GROMOS force field for biomolecular simulation has primarily been developed for performing molecular dynamics (MD) simulations of polypeptides and, to a lesser extent, sugars. When applied to DNA, the 43A1 and 45A3 parameter sets of the years 1996 and 2001 produced rather flexible double‐helical structures, in which the Watson–Crick hydrogen‐bonding content was more limited than expected. To improve on the currently available parameter sets, the nucleotide backbone torsional‐angle parameters and the charge distribution of the nucleotide bases are reconsidered based on quantum‐chemical data. The new 45A4 parameter set resulting from this refinement appears to perform well in terms of reproducing solution NMR data and canonical hydrogen bonding. The deviation between simulated and experimental observables is now of the same order of magnitude as the uncertainty in the experimental values themselves.

Computation of methodology-independent ionic solvation free energies from molecular simulations. II. The hydration free energy of the sodium cation.

The raw ionic solvation free energies computed from atomistic (explicit-solvent) simulations are extremely sensitive to the boundary conditions (finite or periodic system, system shape, and size) and treatment of electrostatic interactions (Coulombic, lattice sum, or cutoff based) used during these simulations. In the present article, it is shown that correction terms can be derived for the effect of (A) an incorrect solvent polarization around the ion due to the use of an approximate (not strictly Coulombic) electrostatic scheme; (B) the finite size or artificial periodicity of the simulated system; (C) an improper summation scheme to evaluate the potential at the ion site and the possible presence of a liquid-vacuum interface in the simulated system. Taking the hydration free energy of the sodium cation as a test case, it is shown that the raw solvation free energies obtained using seven different types of boundary conditions and electrostatic schemes commonly used in explicit-solvent simulations (for a total of 72 simulations differing in the corresponding simulation parameters) can be corrected so as to obtain a consistent value for this quantity.

Molecular Dynamics Simulations of a Reversibly Folding β-Heptapeptide in Methanol: Influence of the Treatment of Long-Range Electrostatic Interactions

Eight 100-ns molecular dynamics simulations of a beta-heptapeptide in methanol at 340 K (within cubic periodic computational boxes of about 6-nm edge) are reported and compared. These simulations were performed with three different charge-state combinations at the peptide termini, one of them with or without a neutralizing chloride counterion, and using either the lattice-sum (LS) or reaction-field (RF) scheme to handle electrostatic interactions. The choice of the electrostatic scheme has essentially no influence on the folding-unfolding equilibrium when the peptide termini are uncharged and only a small influence when the peptide is positively charged at its N-terminus (with or without inclusion of a neutralizing chloride counterion). However, when the peptide is zwitterionic, the LS scheme leads to preferential sampling of the high-dipole folded helical state, whereas the RF scheme leads to preferential sampling of a low-dipole unfolded salt-bridged state. A continuum electrostatics analysis based on the sampled configurations (zwitterionic case) suggests that the LS scheme stabilizes the helical state through artificial periodicity, but that the magnitude of this perturbation is essentially negligible (compared to the thermal energy) for the large box size and relatively polar solvent considered. The results thus provide clear evidence (continuum electrostatics analysis) for the absence of LS artifacts and some indications (still not definitive because of the limited sampling of the folding-unfolding transition) for the presence of RF artifacts in this specific system.

Development of a lattice-sum method emulating nonperiodic boundary conditions for the treatment of electrostatic interactions in molecular simulations: a continuum-electrostatics study.

Artifacts induced by the application of periodic boundary conditions and lattice-sum methods in explicit-solvent simulations of (bio-)molecular systems are nowadays a major concern in the computer-simulation community. The present article reports a first step toward the design of a modified lattice-sum algorithm emulating nonperiodic boundary conditions, and therefore exempt of such periodicity-induced artifacts. This result is achieved here in the (more simple) context of continuum electrostatics. It is shown that an appropriate modification of the periodic Poisson equation and of its boundary conditions leads to a continuum-electrostatics scheme, which, although applied under periodic boundary conditions, exactly mimics the nonperiodic situation. The possible extension of this scheme to explicit-solvent simulations is outlined and its practical implementation will be described in more details in a forthcoming article.