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

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.

Asymmetric enamine catalysis.

The widespread use of controlled molecular-level motion in key natural processes suggests that great rewards could come from bridging the gap between the present generation of synthetic molecular systems, which by and large rely upon electronic and chemical effects to carry out their functions, and the machines of the macroscopic world, which utilize the synchronized movements of smaller parts to perform specific tasks. This is a scientific area of great contemporary interest and extraordinary recent growth, yet the notion of molecular-level machines dates back to a time when the ideas surrounding the statistical nature of matter and the laws of thermodynamics were first being formulated. Here we outline the exciting successes in taming molecular-level movement thus far, the underlying principles that all experimental designs must follow, and the early progress made towards utilizing synthetic molecular structures to perform tasks using mechanical motion. We also highlight some of the issues and challenges that still need to be overcome.

Synthetic molecular motors and mechanical machines.

Nature relies on large molecules to carry out sophisticated chemical operations, such as catalysis, tight and specific binding, directed flow of electrons, or controlled crystallization of inorganic phases. The polymers entrusted with these crucial tasks, mostly proteins but sometimes RNA, are unique relative to other biological and synthetic polymers in that they adopt specific compact conformations that are thermodynamically and kinetically stable. These folding patterns generate “active sites” via precise three-dimensional arrangement of functional groups. In terms of covalent connectivity, the groups that comprise the active site are often widely spaced along the polymer backbone. The remarkable range of chemical capabilities that evolution has elicited from proteins suggests that it might be possible to design analogous capabilities into unnatural polymers that fold into compact and specific conformations. Since biological evolution has operated under many constraints, the functional properties of proteins and RNA should be viewed as merely exemplifying the potential of compactly folded polymers. The chemist’s domain includes all possible combinations of the elements, and the biological realm, vast and complex though it may be, is only a small part of that domain. Therefore, realization of the potential of folding polymers may be limited more by the human imagination than by physical barriers. I use the term “foldamer” to describe any polymer with a strong tendency to adopt a specific compact conformation. Among proteins, the term “compact” is associated with tertiary structure, and there is as yet no synthetic polymer that displays a specific tertiary structure. Protein tertiary structure arises from the assembly of elements of regular secondary structure (helices, sheets, and turns). The first step in foldamer design must therefore be to identify new backbones with well-defined secondary structural preferences. “Well-defined” in this case means that the conformational preference should be displayed in solution by oligomers of modest length, and I will designate as a foldamer any oligomer that meets this criterion. Within the past decade, a handful of research groups have described unnatural oligomers with interesting conformational propensities. The motivations behind such efforts are varied, but these studies suggest a collective, emerging realization that control over oligomer and polymer folding could lead to new types of molecules with useful properties. The purpose of this “manifesto” is to introduce a large audience to the broad research horizons offered by the concept of synthetic foldamers. The path to creating useful foldamers involves several daunting steps. (i) One must identify new polymeric backbones with suitable folding propensities. This goal includes developing a predictively useful understanding of the relationship between the repetitive features of monomer structure and conformational properties at the polymer level. (ii) One must endow the resulting foldamers with interesting chemical functions, by design, by randomization and screening (“evolution”), or by some combination of these two approaches. (iii) For technological utility, one must be able to produce a foldamer efficiently, which will generally include preparation of the constituent monomers in stereochemically pure form and optimization of heteropolymer synthesis. Each of these steps involves fascinating chemical challenges; the first step is the focus of this Account.

Foldamers: A Manifesto

Accurate reproduction of the mechanism of peptide folding in solution and conformational preferences as a function of amino acid sequence is possible with atomic level dynamics simulations. For example, the simulations correctly predict a left-handed 31-helical fold for the β-heptapeptide 1 (the molecular model is shown in the picture) and a right-handed helical fold for the β-hexapeptide 2, as was confirmed by NMR spectroscopy.

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Peptide Folding: When Simulation Meets Experiment

http://bioinf.uab.es/xavier/papers/jmolbiol_280-925.pdf

Reversible Peptide Folding in Solution by Molecular Dynamics Simulation

Large amounts (estimates range from 70 Tg per year to 300 Tg per year) of the potent greenhouse gas methane are oxidized to carbon dioxide in marine sediments by communities of methanotrophic archaea and sulphate-reducing bacteria, and thus are prevented from escaping into the atmosphere. Indirect evidence indicates that the anaerobic oxidation of methane might proceed as the reverse of archaeal methanogenesis from carbon dioxide with the nickel-containing methyl-coenzyme M reductase (MCR) as the methane-activating enzyme. However, experiments showing that MCR can catalyse the endergonic back reaction have been lacking. Here we report that purified MCR from Methanothermobacter marburgensis converts methane into methyl-coenzyme M under equilibrium conditions with apparent V(max) (maximum rate) and K(m) (Michaelis constant) values consistent with the observed in vivo kinetics of the anaerobic oxidation of methane with sulphate. This result supports the hypothesis of 'reverse methanogenesis' and is paramount to understanding the still-unknown mechanism of the last step of methanogenesis. The ability of MCR to cleave the particularly strong C-H bond of methane without the involvement of highly reactive oxygen-derived intermediates is directly relevant to catalytic C-H activation, currently an area of great interest in chemistry.

The key nickel enzyme of methanogenesis catalyses the anaerobic oxidation of methane

Structural prerequisites for the stability of the 31 helix of β-peptides can be defined from inspection of models (Figs. 1 and 2): lateral non-H-substituents in 2- and 3-position on the 3-amino-acid residues of the helix are allowed, axial ones are forbidden. To be able to test this prediction, we synthesized a series of heptapeptide derivatives Boc-(β-HVal-β-HAla-β-HLeu-Xaa-β-HVal-β-HAla-β-HLeu)-OMe 13–22 (Xaa = α- or β-amino-acid residue) and a β-depsipeptide 25 with a central (S)-3-hydroxybutanoic-acid residue (Xaa = –OCH(Me)CH2C(O)–) (Schemes 1 3). Detailed NMR analysis (DQF-COSY, HSQC, HMBC, ROESY, and TOCSY experiments) in methanol solution of the β-hexapeptide H(-β-HVal-β-HAla-β-HLeu)2-OH (1) and of the β-heptapeptide H-β-HVal-β-HAla-β-HLeu-(S,S)-β-HAla(αMe)-β-HVal-β-HAla- β-HLeu-OH (22), with a central (2S,3S)-3-amino-2-methylbutanoic-acid residue, confirm the helical structure of such β-peptides (previously discovered in pyridine solution) (Fig.3 and Tables 1–5). The CD spectra of helical β-peptides, the residues of which were prepared by (retentive) Arndt-Eistert homologation of the (S)- or L-α-amino acids, show a trough at 215 nm. Thus, this characteristic pattern of the CD spectra was taken as an indicator for the presence of a helix in methanol solutions of compounds 13–22 and 25 (including partially and fully deprotected forms) (Figs.4–6). The results fully confirm predicted structural effects: incorporation of a single ‘wrong’ residue ((R)-β-HAla, β-HAib, (R,S)-β-HAla(α Me), or N-Me-β-HAla) in the central position of the β-heptapeptide derivatives A (see 17, 18, 20, or 21, resp.) causes the CD minimum to disappear. Also, the β-heptadepsipetide 25 (missing H-bond) and the β-heptapeptide analogs with a single α-amino-acid moiety in the middle (13 and 14) are not helical, according to this analysis. An interesting case is the heptapeptide 15 with the central achiral, unsubstituted 3-aminopropanoic-acid moiety: helical conformation appears to depend upon the presence or absence of terminal protection and upon the solvent (MeOH vs. MeOH/H2O).

Probing the Helical Secondary Structure of Short‐Chain β‐Peptides

Components of a toolbox with predictable secondary structural elements: β-peptides. The β-peptide shown here with proteinogenic side chains adopts a parallel pleated sheet structure in the solid state upon incorporation of suitably configured β-amino acids. When a β-dipeptide turn segment is incorporated in the center, a hairpin is formed in solution.

Bernhard Jaun

Papers

Peptide Folding: When Simulation Meets Experiment

Reversible Peptide Folding in Solution by Molecular Dynamics Simulation

The key nickel enzyme of methanogenesis catalyses the anaerobic oxidation of methane

Probing the Helical Secondary Structure of Short‐Chain β‐Peptides

Pleated Sheets and Turns of β-Peptides with Proteinogenic Side Chains.