Andreas P. Eichenberger

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.

Architecture, implementation and parallelisation of the GROMOS software for biomolecular simulation☆

Abstract In this work the design of the latest version of the GROMOS software for biomolecular simulation, GROMOS11 is discussed. Detailed organisation and class descriptions of the MD++ simulation program and the GROMOS++ analysis package are given. It is shown how the code was documented, how it can be easily modified and extended, how debugging of it is carried out. Additional efficiency and parallelisation concepts are presented and benchmarked.

GROMOS++ Software for the Analysis of Biomolecular Simulation Trajectories

GROMOS++ is a set of C++ programs for pre- and postprocessing of molecular dynamics simulation trajectories and as such is part of the GROningen MOlecular Simulation software for (bio)molecular simulation. It contains more than 70 programs that can be used to prepare data for the production of molecular simulation trajectories and to analyze these. These programs are reviewed and the various structural, dynamic, and thermodynamic quantities that can be analyzed using time series, correlation functions, and distributions are described together with technical aspects of their implementation in GROMOS. A few examples of the use of GROMOS++ for the analysis of MD trajectories are given. A full list of all GROMOS++ programs, together with an indication of their capabilities, is given in the Appendix .

Multi-Resolution Simulation of Biomolecular Systems: A Review of Methodological Issues

Theoretical-computational modeling with an eye to explaining experimental observations in regard to a particular chemical phenomenon or process requires choices concerning essential degrees of freedom and types of interactions and the generation of a Boltzmann ensemble or trajectories of configurations. Depending on the degrees of freedom that are essential to the process of interest, for example, electronic or nuclear versus atomic, molecular or supra-molecular, quantum- or classical-mechanical equations of motion are to be used. In multi-resolution simulation, various levels of resolution, for example, electronic, atomic, supra-atomic or supra-molecular, are combined in one model. This allows an enhancement of the computational efficiency, while maintaining sufficient detail with respect to particular degrees of freedom. The basic challenges and choices with respect to multi-resolution modeling are reviewed and as an illustration the differential catalytic properties of two enzymes with similar folds but different substrates with respect to these substrates are explored using multi-resolution simulation at the electronic, atomic and supra-molecular levels of resolution.

Biomolecular structure refinement using the GROMOS simulation software

For the understanding of cellular processes the molecular structure of biomolecules has to be accurately determined. Initial models can be significantly improved by structure refinement techniques. Here, we present the refinement methods and analysis techniques implemented in the GROMOS software for biomolecular simulation. The methodology and some implementation details of the computation of NMR NOE data, 3J-couplings and residual dipolar couplings, X-ray scattering intensities from crystals and solutions and neutron scattering intensities used in GROMOS is described and refinement strategies and concepts are discussed using example applications. The GROMOS software allows structure refinement combining different types of experimental data with different types of restraining functions, while using a variety of methods to enhance conformational searching and sampling and the thermodynamically calibrated GROMOS force field for biomolecular simulation.

Solvating atomic level fine-grained proteins in supra-molecular level coarse-grained water for molecular dynamics simulations

Simulation of the dynamics of a protein in aqueous solution using an atomic model for both the protein and the many water molecules is still computationally extremely demanding considering the time scale of protein motions. The use of supra-atomic or supra-molecular coarse-grained (CG) models may enhance the computational efficiency, but inevitably at the cost of reduced accuracy. Coarse-graining solvent degrees of freedom is likely to yield a favourable balance between reduced accuracy and enhanced computational speed. Here, the use of a supra-molecular coarse-grained water model that largely preserves the thermodynamic and dielectric properties of atomic level fine-grained (FG) water in molecular dynamics simulations of an atomic model for four proteins is investigated. The results of using an FG, a CG, an implicit, or a vacuum solvent environment of the four proteins are compared, and for hen egg-white lysozyme a comparison to NMR data is made. The mixed-grained simulations do not show large differences compared to the FG atomic level simulations, apart from an increased tendency to form hydrogen bonds between long side chains, which is due to the reduced ability of the supra-molecular CG beads that represent five FG water molecules to make solvent-protein hydrogen bonds. But, the mixed-grained simulations are at least an order of magnitude faster than the atomic level ones.

Structural Effects of an Atomic-Level Layer of Water Molecules around Proteins Solvated in Supra-Molecular Coarse-Grained Water

Atomistic molecular dynamics simulations of proteins in aqueous solution are still limited to the multinanosecond time scale and multinanometer range by computational cost. Combining atomic solutes with a supra-molecular solvent model in hybrid fine-grained/coarse-grained (FG/CG) simulations allows atomic detail in the region of interest while being computationally more efficient. A recent comparison of the properties of four proteins in CG water versus FG water showed the preservation of the secondary and tertiary structure with a computational speed-up of at least an order of magnitude. However, an increased occurrence of hydrogen bonds between side chains was observed due to a lack of hydrogen-bonding partners in the supra-molecular solvent. Here, the introduction of a FG water layer around the protein to recover the hydrogen-bonding pattern of the atomistic simulations is studied. Three layer thicknesses of 0.2, 0.4, and 0.8 nm are considered. A layer thickness of 0.8 nm is found sufficient to recover the behavior of the proteins in the atomistic simulations, whereas the hybrid simulation is still three times more efficient than the atomistic one and the cutoff radius for nonbonded interactions could be increased from 1.4 to 2.0 nm.

On the calculation of 3 J αβ-coupling constants for side chains in proteins

Structural knowledge about proteins is mainly derived from values of observables, measurable in NMR spectroscopic or X-ray diffraction experiments, i.e. absorbed or scattered intensities, through theoretically derived relationships between structural quantities such as atom positions or torsional angles on the one hand and observable quantities such as squared structure factor amplitudes, NOE intensities or 3J-coupling constants on the other. The standardly used relation connecting 3J-couplings to torsional angles is the Karplus relation, which is used in protein structure refinement as well as in the evaluation of simulated properties of proteins. The accuracy of the simple and generalised Karplus relations is investigated using side-chain structural and 3Jαβ-coupling data for three different proteins, Plastocyanin, Lysozyme, and FKBP, for which such data are available. The results show that the widely used Karplus relations are only a rough estimate for the relation between 3Jαβ-couplings and the corresponding χ1-angle in proteins.

A simple, efficient polarizable molecular model for liquid carbon tetrachloride

A one-site and a five-site polarizable model for liquid carbon tetrachloride (CCl4) is presented. They are based on a non-polarizable model consisting of five van der Waals sites not carrying any partial charges. In the one-site model, a charge on a spring with a polarizability of 11.1 nm3 was attached to the carbon to make the model polarizable, while in the five-site model polarizabilities  nm3 and  nm3 were added to the carbon and chlorine atoms, respectively. Both models exactly reproduce the experimental static dielectric permittivity of 2.24 at 293 K and 1 atm. This quantity was calculated by applying a homogeneous external electric field of varying strength. The one-site polarizable model is only about 1.7 times more computationally expensive than the non-polarizable one and is compatible with the GROMOS force field. A selected set of thermodynamic, dynamic and structural quantities was calculated and compared to experiment.

Structure of hen egg-white lysozyme solvated in TFE/water: a molecular dynamics simulation study based on NMR data.

Various experimental studies of hen egg white lysozyme (HEWL) in water and TFE/water clearly indicate structural differences between the native state and TFE state of HEWL, e.g. the helical content of the protein in the TFE state is much higher than in the native state. However, the available detailed NMR studies were not sufficient to determine fully a structure of HEWL in the TFE state. Different molecular dynamics (MD) simulations, i.e. at room temperature, at increased temperature and using proton–proton distance restraints derived from NMR NOE data, have been used to generate configurational ensembles corresponding to the TFE state of HEWL. The configurational ensemble obtained at room temperature using atom-atom distance restraints measured for HEWL in TFE/water solution satisfies the experimental data and has the lowest protein energy. In this ensemble residues 50–58, which are part of the β-sheet in native HEWL, adopt fluctuating α-helical secondary structure.