Philippe H. Hünenberger

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.

Comparison of four methods to compute the dielectric permittivity of liquids from molecular dynamics simulations

Four methods to compute the dielectric permittivity e of a liquid from molecular simulations are compared in the context of the simple point charge (SPC) water model. In the first method (unrestrained method), e is evaluated from the fluctuations of the box dipole moment M, monitored during a single equilibrium simulation. In the three other methods, e is evaluated from the probability distribution p(M) of the dipole moment norm. This distribution is itself evaluated in three different ways: (i) from multiple simulations involving a M-dependent biasing potential (umbrella-sampling method), (ii) from multiple simulations involving a constrained dipole moment norm (M-constraint method), or (iii) from fitting of incomplete p(M) estimates to a Maxwell distribution (fitting method). The four methods are shown to converge to an identical estimate of e=61±1 for SPC water (256 molecules, reaction-field electrostatics). The convergence properties, advantages, and drawbacks of the different methods are analyzed in ...

Ewald artifacts in computer simulations of ionic solvation and ion–ion interaction: A continuum electrostatics study

The use of Ewald and related methods to handle electrostatic interactions in explicit-solvent simulations of solutions imposes an artificial periodicity on systems which are inherently nonperiodic. The consequences of this approximation should be assessed, since they may crucially affect the reliability of those computer simulations. In the present study, we propose a general method based on continuum electrostatics to investigate the nature and magnitude of periodicity-induced artifacts. As a first example, this scheme is applied to the solvation free-energy of a spherical ion. It is found that artificial periodicity reduces the magnitude of the ionic solvation free-energy, because the solvent in the periodic copies of the central unit cell is perturbed by the periodic copies of the ion, thus less available to solvate the central ion. In the limit of zero ionic radius and infinite solvent permittivity, this undersolvation can be corrected by adding the Wigner self-energy term to the solvation free-energy...

Martini Coarse-Grained Force Field: Extension to Carbohydrates.

We present an extension of the Martini coarse-grained force field to carbohydrates. The parametrization follows the same philosophy as was used previously for lipids and proteins, focusing on the reproduction of partitioning free energies of small compounds between polar and nonpolar phases. The carbohydrate building blocks considered are the monosaccharides glucose and fructose and the disaccharides sucrose, trehalose, maltose, cellobiose, nigerose, laminarabiose, kojibiose, and sophorose. Bonded parameters for these saccharides are optimized by comparison to conformations sampled with an atomistic force field, in particular with respect to the representation of the most populated rotameric state for the glycosidic bond. Application of the new coarse-grained carbohydrate model to the oligosaccharides amylose and Curdlan shows a preservation of the main structural properties with 3 orders of magnitude more efficient sampling than the atomistic counterpart. Finally, we investigate the cryo- and anhydro-protective effect of glucose and trehalose on a lipid bilayer and find a strong decrease of the melting temperature, in good agreement with both experimental findings and atomistic simulation studies.

A new GROMOS force field for hexopyranose‐based carbohydrates

A new parameter set (referred to as 45A4) is developed for the explicit‐solvent simulation of hexopyranose‐based carbohydrates. This set is compatible with the most recent version of the GROMOS force field for proteins, nucleic acids, and lipids, and the SPC water model. The parametrization procedure relies on: (1) reassigning the atomic partial charges based on a fit to the quantum‐mechanical electrostatic potential around a trisaccharide; (2) refining the torsional potential parameters associated with the rotations of the hydroxymethyl, hydroxyl, and anomeric alkoxy groups by fitting to corresponding quantum‐mechanical profiles for hexopyranosides; (3) adapting the torsional potential parameters determining the ring conformation so as to stabilize the (experimentally predominant) 4C1 chair conformation. The other (van der Waals and nontorsional covalent) parameters and the rules for third and excluded neighbors are taken directly from the most recent version of the GROMOS force field (except for one additional exclusion). The new set is general enough to define parameters for any (unbranched) hexopyranose‐based mono‐, di‐, oligo‐ or polysaccharide. In the present article, this force field is validated for a limited set of monosaccharides (α‐ and β‐D‐glucose, α‐ and β‐D‐galactose) and disaccharides (trehalose, maltose, and cellobiose) in solution, by comparing the results of simulations to available experimental data. More extensive validation will be the scope of a forthcoming article.

Effect of artificial periodicity in simulations of biomolecules under Ewald boundary conditions: a continuum electrostatics study

Ewald and related methods are nowadays routinely used in explicit-solvent simulations of biomolecules, although they impose an artificial periodicity in systems which are inherently non-periodic. The consequences of this approximation should be assessed, since they may crucially affect the reliability of computer simulations under Ewald boundary conditions. In the present study we use a method based on continuum electrostatics to investigate the nature and magnitude of possible periodicity-induced artifacts on the potentials of mean force for conformational equilibria in biomolecules. Three model systems and pathways are considered: polyalanine oligopeptides (unfolding), a DNA tetranucleotide (separation of the strands), and the protein Sac7d (conformations from a molecular dynamics simulation). Artificial periodicity may significantly affect these conformational equilibria, in each case stabilizing the most compact conformation of the biomolecule. Three factors enhance periodicity-induced artifacts: (i) a solvent of low dielectric permittivity; (ii) a solute size which is non-negligible compared to the size of the unit cell; and (iii) a non-neutral solute. Neither the neutrality of the solute nor the absence of charge pairs at distances exceeding half the edge of the unit cell do guarantee the absence of artifacts.

Trehalose Protein Interaction in Aqueous Solution

A variety of sugars are known to enhance the stability of biomaterials. Trehalose, a nonreducing disaccharide composed of two α, α(1 → 1)‐linked D‐glucopyranose units, appears to be one of the most effective protectants. Both in vivo and in vitro, trehalose protects biostructures such as proteins and membranes from damage due to dehydration, heat, or cold. However, despite the significant amount of experimental data on this disaccharide, no clear picture of the molecular mechanism responsible for its stabilizing properties has emerged yet. Three major hypotheses (water–trehalose hydrogen‐bond replacement, coating by a trapped water layer, and mechanical inhibition of the conformational fluctuations) have been proposed to explain the stabilizing effect of trehalose on proteins. To investigate the nature of protein–trehalose–water interactions in solution at the molecular level, two molecular dynamics simulations of the protein lysozyme in solution at room temperature have been carried out, one in the presence (about 0.5 M) and one in the absence of trehalose. The results show that the trehalose molecules cluster and move toward the protein, but neither completely expel water from the protein surface nor form hydrogen bonds with the protein. Furthermore, the coating by trehalose does not significantly reduce the conformational fluctuations of the protein compared to the trehalose‐free system. Based on these observations, a model is proposed for the interaction of trehalose molecules with a protein in moderately concentrated solutions, at room temperature and on the nanosecond timescale. Proteins 2004;55:177–186.

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.