Daniel Trzesniak

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.

Exact Distances and Internal Dynamics of Perdeuterated Ubiquitin from NOE Buildups

It is proposed to convert nuclear Overhauser effects (NOEs) into relatively precise distances for detailed structural studies of proteins. To this purpose, it is demonstrated that the measurement of NOE buildups between amide protons in perdeuterated human ubiquitin using a designed (15)N-resolved HMQC-NOESY experiment enables the determination of (1)H(N)-(1)H(N) distances up to 5 A with high accuracy and precision. These NOE-derived distances have an experimental random error of approximately 0.07 A, which is smaller than the pairwise rmsd (root-mean-square deviation) of 0.24 A obtained with corresponding distances extracted from either an NMR or an X-ray structure (pdb codes: 1D3Z and 1UBQ), and also smaller than the pairwise rmsd between distances from X-ray and NMR structures (0.15 A). Because the NOE contains both structural and dynamical information, a comparison between the 3D structures and NOE-derived distances may also give insights into through-space dynamics. It appears that the extraction of motional information from NOEs by comparison to the X-ray structure or the NMR structure is challenging because the motion may be masked by the quality of the structures. Nonetheless, a detailed analysis thereof suggests motions between beta-strands and large complex motions in the alpha-helix of ubiquitin. The NOE-derived motions are, however, of smaller amplitude and possibly of a different character than those present in a 20 ns molecular dynamic simulation of ubiquitin in water using the GROMOS force field. Furthermore, a recently published set of structures representing the conformational distribution over time scales up to milliseconds (pdb: 2K39) does not satisfy the NOEs better than the single X-ray structure. Hence, the measurement of possibly thousands of exact NOEs throughout the protein may serve as an excellent probe toward a correct representation of both structure and dynamics of proteins.

Computer simulation studies on the solvation of aliphatic hydrocarbons in 6.9 M aqueous urea solution

We report solvation free energies for six aliphatic hydrocarbons in 6.9 M urea–water mixture obtained by molecular dynamics simulations. Hydrocarbon transfer free energies from water to the urea solution are also presented. Our calculations predict that, except for methane, aliphatic hydrocarbons are more soluble in 6.9 M urea than in water, in satisfactory agreement (deviations smaller than 2 kJ mol−1) with experimental transfer free energies reported in the literature. An analysis of solute–solvent contributions to the solvation enthalpies and entropies indicates that urea enhances the solvation of hydrocarbons compared to pure water due to a favourable van der Waals interaction with the solute whereas the solute–solvent entropy opposes the hydrocarbon transfer. Radial distribution functions between the solute and the solvent are examined and together with an analysis based on Kirkwood–Buff theory indicate a weak preferential urea–hydrocarbon binding. The entropic penalty related with solute urea association is discussed in terms of the molecular interactions in solution.

Protein Under Pressure: Molecular Dynamics Simulation of the Arc Repressor

Experimental nuclear magnetic resonance results for the Arc Repressor have shown that this dimeric protein dissociates into a molten globule at high pressure. This structural change is accompanied by a modification of the hydrogen‐bonding pattern of the intermolecular β‐sheet: it changes its character from intermolecular to intramolecular with respect to the two monomers. Molecular dynamics simulations of the Arc Repressor, as a monomer and a dimer, at elevated pressure have been performed with the aim to study this hypothesis and to identify the major structural and dynamical changes of the protein under such conditions. The monomer appears less stable than the dimer. However, the complete dissociation has not been seen because of the long timescale needed to observe this phenomenon. In fact, the protein structure altered very little when increasing the pressure. It became slightly compressed and the dynamics of the side‐chains and the unfolding process slowed down. Increasing both, temperature and pressure, a tendency of conversion of intermolecular into intramolecular hydrogen bonds in the β‐sheet region has been detected, supporting the mentioned hypothesis. Also, the onset of denaturation of the separated chains was observed. Proteins 2006.

Catalytic mechanism of cyclophilin as observed in molecular dynamics simulations: pathway prediction and reconciliation of X-ray crystallographic and NMR solution data.

Cyclophilins are proteins that catalyze X‐proline cis–trans interconversion, where X represents any amino acid. Its mechanism of action has been investigated over the past years but still generates discussion, especially because until recently structures of the ligand in the cis and trans conformations for the same system were lacking. X‐ray crystallographic structures for the complex cyclophilin A and HIV‐1 capsid mutants with ligands in the cis and trans conformations suggest a mechanism where the N‐terminal portion of the ligand rotates during the cis–trans isomerization. However, a few years before, a C‐terminal rotating ligand was proposed to explain NMR solution data. In the present study we use molecular dynamics (MD) simulations to generate a trans structure starting from the cis structure. From simulations starting from the cis and trans structures obtained through the rotational pathways, the seeming contradiction between the two sets of experimental data could be resolved. The simulated N‐terminal rotated trans structure shows good agreement with the equivalent crystal structure and, moreover, is consistent with the NMR data. These results illustrate the use of MD simulation at atomic resolution to model structural transitions and to interpret experimental data.

Analysis of neo -pentane–urea pair potentials of mean force in aqueous urea

Urea is often used as a denaturant in protein (un)folding studies because it alters the way hydrophobic solutes and water affect one another. The solvation structure of neo-pentane and urea in 6.9 M urea aqueous solution are investigated by analysing the neo-pentane–urea potential of mean force (PMF) as a function of the neo-pentane–urea separation obtained from molecular dynamics simulations. The PMF is decomposed into its enthalpic (H) and entropic (S) contributions, which are further separated into solute (neo-pentane–urea pair) and solvent (urea, water) contributions. Statistical-mechanical, enthalpic and entropic contributions arising from solvent–solvent interactions do not contribute directly to the PMF because they exactly cancel each other. By excluding the solvent–solvent parts, it is seen that the first minimum in the PMF is due to a combination of contributions coming from the neo-pentane–urea pair self-enthalpy and from the entropy related to the interaction of the neo-pentane–urea pair solute with the remaining solvent molecules. The enthalpy of a neo-pentane–urea pair solute and the remaining urea and water molecules acts against neo-pentane–urea association because this association prohibits the remaining solvent from interacting with the urea molecule belonging to the solute. In addition, ranges of interest in the PMF are structurally and energetically characterized in terms of hydrogen bonding, non-bonded energies and number of neighbouring molecules of a given type. This leads to a consistent thermodynamic and structural picture of hydrophobic co-solvent interaction in aqueous urea.