Dirk Bakowies

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.

Water in protein cavities: A procedure to identify internal water and exchange pathways and application to fatty acid-binding protein

A computational approach based on Delaunay triangulation is presented to identify internal water molecules in proteins and to capture pathways of exchange with the bulk. The implemented procedure is computationally efficient and can easily be applied to long molecular dynamics trajectories of protein simulations. In an application to fatty acid‐binding protein in apo‐form and with bound palmitate, several protein orifices known from crystal structures have been confirmed to be major portals of solvent exchange. Differences between the two forms of the protein are observed and discussed. Proteins 2002;47:534–545.

Accurate extrapolation of electron correlation energies from small basis sets

A new two-point scheme is proposed for the extrapolation of electron correlation energies obtained with small basis sets. Using the series of correlation-consistent polarized valence basis sets, cc-pVXZ, the basis set truncation error is expressed as deltaE(X) proportional, variant(X + xi(i))(-gamma). The angular momentum offset xi(i) captures differences in effective rates of convergence previously observed for first-row molecules. It is based on simple electron counts and tends to values close to 0 for hydrogen-rich compounds and values closer to 1 for pure first-row compounds containing several electronegative atoms. The formula is motivated theoretically by the structure of correlation-consistent basis sets which include basis functions up to angular momentum L = X-1 for hydrogen and helium and up to L = X for first-row atoms. It contains three parameters which are calibrated against a large set of 105 reference molecules (H, C, N, O, F) for extrapolations of MP2 and CCSD valence-shell correlation energies from double- and triple-zeta (DT) and triple- and quadruple-zeta (TQ) basis sets. The new model is shown to be three to five times more accurate than previous two-point schemes using a single parameter, and (TQ) extrapolations are found to reproduce a small set of available R12 reference data better than even (56) extrapolations using the conventional asymptotic limit formula deltaE(X) proportional, variantX(-3). Applications to a small selection of boron compounds and to neon show very satisfactory results as well. Limitations of the model are discussed.

Ab initio thermochemistry using optimal-balance models with isodesmic corrections: the ATOMIC protocol.

A theoretical composite approach, termed ATOMIC for Ab initio Thermochemistry using Optimal-balance Models with Isodesmic Corrections, is introduced for the calculation of molecular atomization energies and enthalpies of formation. Care is taken to achieve optimal balance in accuracy and cost between the various components contributing to high-level estimates of the fully correlated energy at the infinite-basis-set limit. To this end, the energy at the coupled-cluster level of theory including single, double, and quasiperturbational triple excitations is decomposed into Hartree-Fock, low-order correlation (MP2, CCSD), and connected-triples contributions and into valence-shell and core contributions. Statistical analyses for 73 representative neutral closed-shell molecules containing hydrogen and at least three first-row atoms (CNOF) are used to devise basis-set and extrapolation requirements for each of the eight components to maintain a given level of accuracy. Poples concept of bond-separation reactions is implemented in an ab initio framework, providing for a complete set of high-level precomputed isodesmic corrections which can be used for any molecule for which a valence structure can be drawn. Use of these corrections is shown to lower basis-set requirements dramatically for each of the eight components of the composite model. A hierarchy of three levels is suggested for isodesmically corrected composite models which reproduce atomization energies at the reference level of theory to within 0.1 kcal/mol (A), 0.3 kcal/mol (B), and 1 kcal/mol (C). Large-scale statistical analysis shows that corrections beyond the CCSD(T) reference level of theory, including coupled-cluster theory with fully relaxed connected triple and quadruple excitations, first-order relativistic and diagonal Born-Oppenheimer corrections can normally be dealt with using a greatly simplified model that assumes thermoneutral bond-separation reactions and that reduces the estimate of these corrections to the simple task of adding up bond increments. Preliminary validation with experimental enthalpies of formation using the subset of neutral closed-shell (HCNOF) species contained in the G3/99 test set indicates that the ATOMIC protocol performs slightly better than the popular G3 approach. The newly introduced protocol does not require empirical calibration, however, and it is still efficient enough to be applied routinely to molecules with 10 or 20 nonhydrogen atoms.

Molecular dynamics simulation of lipid bilayers with GROMOS96: Application of surface tension

The GROMOS96 force fields 45A3 and 53A5, when applied to dipalmitoylphosphatidylcholine (DPPC) membranes, have a tendency to result in a reduced area per lipid in constant pressure simulations. The application of surface tension is effective in increasing the area per lipid, a measure of the phase of the membrane, but only if the area is already close to the experimental range. Therefore the surface tension cannot compensate for strong inadequacies in the force-field parameters. The behaviour of the 45A3 force field from long NP n γT simulations of tens of nanoseconds is analysed over a range of different surface tensions. Comparisons are made with the corresponding NP n AT simulations.

β-Peptides with Different Secondary-Structure Preferences: How Different Are Their Conformational Spaces?

The conformational spaces accessible to two β-hexapeptides in MeOH at 298 K and 340 K are investigated by molecular-dynamics simulation with an atomistic model of both solute and solvent. The structural properties of these peptides have been previously studied by NMR in MeOH at room temperature. The experimental data could be fitted to a model (P)-12/10-helix for one of the peptides and a model hairpin with a ten-membered H-bonded turn for the other. The goal of the present work is to determine whether the conformational spaces accessible to these two peptides of seemingly different conformational properties contain any common regions. In other words, to what extent are the evident differences found at the macroscopic level also present at the microscopic structural level? It is found that, for the two peptides studied, the conformational spaces sampled in the respective simulations show significant overlap.