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.

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GROMACS: Fast, flexible, and free

CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecu- lar simulation program. It has been developed over the last three decades with a primary focus on molecules of bio- logical interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estima- tors, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. The CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numer- ous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983.

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CHARMM: the biomolecular simulation program.

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.

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

AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules

We present the first global parameterization and validation of a novel charge model, called AM1-BCC, which quickly and efficiently generates high-quality atomic charges for computer simulations of organic molecules in polar media. The goal of the charge model is to produce atomic charges that emulate the HF/6-31G* electrostatic potential (ESP) of a molecule. Underlying electronic structure features, including formal charge and electron delocalization, are first captured by AM1 population charges; simple additive bond charge corrections (BCCs) are then applied to these AM1 atomic charges to produce the AM1-BCC charges. The parameterization of BCCs was carried out by fitting to the HF/6-31G* ESP of a training set of >2700 molecules. Most organic functional groups and their combinations were sampled, as well as an extensive variety of cyclic and fused bicyclic heteroaryl systems. The resulting BCC parameters allow the AM1-BCC charging scheme to handle virtually all types of organic compounds listed in The Merck Index and the NCI Database. Validation of the model was done through comparisons of hydrogen-bonded dimer energies and relative free energies of solvation using AM1-BCC charges in conjunction with the 1994 Cornell et al. forcefield for AMBER.(13) Homo- and hetero-dimer hydrogen-bond energies of a diverse set of organic molecules were reproduced to within 0.95 kcal/mol RMS deviation from the ab initio values, and for DNA dimers the energies were within 0.9 kcal/mol RMS deviation from ab initio values. The calculated relative free energies of solvation for a diverse set of monofunctional isosteres were reproduced to within 0.69 kcal/mol of experiment. In all these validation tests, AMBER with the AM1-BCC charge model maintained a correlation coefficient above 0.96. Thus, the parameters presented here for use with the AM1-BCC method present a fast, accurate, and robust alternative to HF/6-31G* ESP-fit charges for general use with the AMBER force field in computer simulations involving organic small molecules.

Fast, efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation

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

The mathematical formulation, parametrization scheme, and structural results of a new, generally applicable molecular force field are presented. The central features are a scheme for automatic parameter assignments, the consistent united-atom approximation, the absence of atom types other than elements, the replacement of electrostatic terms by geometrical hydrogen-bonding terms, the concomitant lack of a need for partial atomic charge assignment and the strict adherence to a finite-range design. As a consequence of omitting all hydrogen atoms, optimal hydrogen-bond patterns are computed dynamically by appropriate network analyses. For a test set of 1589 structures, selected from the Cambridge Structural Database solely on the grounds of a given element list and criteria for high structure refinement, the agreements are on average 2 pm for bonds, 2 degrees for valence angles and 10 to 20 pm for the root-mean-square deviation of atom positions, depending somewhat on size and flexibility of the structures. More qualitative testing of large-scale structural properties of the force field on proteins and DNA oligomers revealed satisfactory performance.

MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry

Predicting plasma protein binding of drugs: a new approach.

The MM-PBSA approach has become a popular method for calculating binding affinities of biomolecular complexes. Published application examples focus on small test sets and few proteins and, hence, are of limited relevance in assessing the general validity of this method. To further characterize MM-PBSA, we report on a more extensive study involving a large number of ligands and eight different proteins. Our results show that applying the MM-PBSA energy function to a single, relaxed complex structure is an adequate and sometimes more accurate approach than the standard free energy averaging over molecular dynamics snapshots. The use of MM-PBSA on a single structure is shown to be valuable (a) as a postdocking filter in further enriching virtual screening results, (b) as a helpful tool to prioritize de novo design solutions, and (c) for distinguishing between good and weak binders (DeltapIC(50) > or = 2-3), but rarely to reproduce smaller free energy differences.

Validation and use of the MM-PBSA approach for drug discovery.

A system which shows a relatively large blue-phase range is investigated. Owing to the small value of the cholesteric pitch the blue-phase shows no Bragg-reflections in visible light. Nevertheless, electric-field induced birefringence shows quite large values. The response times are a few tens of microseconds below 10°C. Crude estimates of the effects lead to values reasonably close to the experimental ones. Zero voltage birefringence effects are encountered, field induced and slowly decaying at higher temperatures and surface induced at lower temperatures where a uniaxial phase appears to be stable.

Paul R. Gerber

Papers

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

MAB, a generally applicable molecular force field for structure modelling in medicinal chemistry

Predicting plasma protein binding of drugs: a new approach.

Validation and use of the MM-PBSA approach for drug discovery.

Electro-Optical Effects of a Small-Pitch Blue-Phase System