PubMed Health⌕ Search

Biomedical subjects

Daniel Trzesniak

Publications and source records attributed to Daniel Trzesniak.

9 recordsLinked to original sources
PubMed2007

A comparison of methods to compute the potential of mean force.

Most processes occurring in a system are determined by the relative free energy between two or more states because the free energy is a measure of the probability of finding the system in a given state. When the two states of interest are connected by a pathway, usually called reaction coordinate, along which the free-energy profile is determined, this profile or potential of mean force (PMF) will also yield the relative free energy of the two states. Twelve different methods to compute a PMF are reviewed and compared, with regard to their precision, for a system consisting of a pair of methane molecules in aqueous solution. We analyze all combinations of the type of sampling (unbiased, umbrella-biased or constraint-biased), how to compute free energies (from density of states or force averaging) and the type of coordinate system (internal or Cartesian) used for the PMF degree of freedom. The method of choice is constraint-bias simulation combined with force averaging for either an internal or a Cartesian PMF degree of freedom.

Journal Article↗
PubMed2006

Simulation of an all-beta 3-icosapeptide containing the 20 proteinogenic side chains: effect of temperature, pH, counterions, solvent, and force field on helix stability.

Simulations of various beta-peptides have in the last years clarified several issues concerning peptide folding equilibria and interpretation of experimental data, especially from NMR and CD spectroscopy. These simulations involved different temperatures, pH-values, ionic strengths, solvents, and force-field parameters, but a variation of these factors for one beta-peptide has not yet been done. To investigate the influence of varying these factors, we analyze the helix stability of an all-beta3-icosapeptide bearing all 20 proteinogenic amino acid side chains, which is experimentally observed to fold into a 3(14)-helix in methanol but not in water. Structural aspects, such as hydrogen-bonded rings and salt bridges, are discussed and a comparison with NMR primary (NOE distance bounds and 3J-values) and secondary (NMR derived model structures) data is made. We further investigate the reasons for the 3(14)-helix stability/instability in methanol/water. Of all factors studied, the presence of counterions seems to be the one inducing most significant effects in the simulations.

Computer Simulation↗
PubMed2006

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 beta-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 beta-sheet region has been detected, supporting the mentioned hypothesis. Also, the onset of denaturation of the separated chains was observed.

Amino Acid Sequence↗
PubMed2006

Enthalpy-entropy compensation in the effects of urea on hydrophobic interactions.

By comparison of neopentane pair potentials of mean force (PMFs) in room temperature water and 6.9 molar aqueous urea, it was recently shown that urea molecules affect the PMF minima in an unexpected way (Lee, M.-E.; van der Vegt, N. F. A. J. Am. Chem. Soc. 2006, 128, 4948). While the first PMF minimum in urea solution has an identical shape and depth to those of the corresponding minimum in water, the second minimum in urea solution is broader, deeper, and shifted out to a slightly larger distance. Here, we present a study of the enthalpic and entropic contributions to these PMFs. Its significance for understanding the driving forces responsible for thermodynamically favorable neopentane contact and solvent-separated distances in urea solution is discussed. We propose that the solute-solvent entropy and solute-solvent enthalpy changes should be analyzed for obtaining an unambiguous molecular-scale picture. In urea solution, enthalpy-entropy compensation effects associated with structural solvent reorganization processes are large, causing changes of the system's enthalpy and entropy with hydrophobic pair separation to be very different from the solute-solvent enthalpy and entropy changes. The entropies are discussed in terms of the molecular-scale solvent reorganization processes.

Solvents↗
PubMed2006

Biomolecular modeling: Goals, problems, perspectives.

Computation based on molecular models is playing an increasingly important role in biology, biological chemistry, and biophysics. Since only a very limited number of properties of biomolecular systems is actually accessible to measurement by experimental means, computer simulation can complement experiment by providing not only averages, but also distributions and time series of any definable quantity, for example, conformational distributions or interactions between parts of systems. Present day biomolecular modeling is limited in its application by four main problems: 1) the force-field problem, 2) the search (sampling) problem, 3) the ensemble (sampling) problem, and 4) the experimental problem. These four problems are discussed and illustrated by practical examples. Perspectives are also outlined for pushing forward the limitations of biomolecular modeling.

Computer Simulation↗
PubMed2006

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.

Catalysis↗
PubMed2005

Interpreting NMR data for beta-peptides using molecular dynamics simulations.

NMR is one of the most used techniques to resolve structure of proteins and peptides in solution. However, inconsistencies may occur due to the fact that a polypeptide may adopt more than one conformation. Since the NOE distance bounds and (3)J-values used in such structure determination represent a nonlinear average over the total ensemble of conformers, imposition of NOE or (3)J-value restraints to obtain one unique conformation is not an appropriate procedure in such cases. Here, we show that unrestrained MD simulation of a solute in solution using a high-quality force field yields a conformational ensemble that is largely compatible with the experimental NMR data on the solute. Four 100 ns MD simulations of two forms of a nine-residue beta-peptide in methanol at two temperatures produced conformational ensembles that were used to interpret the NMR data on this molecule and resolve inconsistencies between the experimental NOEs. The protected and unprotected forms of the beta-peptide adopt predominantly a 12/10-helix in agreement with the qualitative interpretation of the NMR data. However, a particular NOE was not compatible with this helix indicating the presence of other conformations. The simulations showed that 3(14)()-helical structures were present in the ensemble of the unprotected form and that their presence correlates with the fulfillment of the particular NOE. Additionally, all inter-hydrogen distances were calculated to compare NOEs predicted by the simulations to the ones observed experimentally. The MD conformational ensembles allowed for a detailed and consistent interpretation of the experimental data and showed the small but specific conformational differences between the protected and unprotected forms of the peptide.

Computer Simulation↗
PubMed2005

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.

Algorithms↗