Biomedical subjects

Wilfred F van Gunsteren

Publications and source records attributed to Wilfred F van Gunsteren.

At least 19 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↗

PubMed2007

Simulation of beta-depsipeptides: the effect of missing hydrogen-bond donors on their folding equilibria.

beta-Depsipeptides are beta-peptides in which one or more peptide linkages are replaced by ester linkages, resulting in a loss of a hydrogen-bond donor (N--H) and weakening of the corresponding carbonyl hydrogen-bond acceptor moiety. The effects of three of such peptide by ester substitutions in a hepta-beta-peptide upon its (un)folding equilibrium in methanol solution are investigated using molecular dynamics simulations and compared to experimental data from NMR spectroscopy. The simulated conformational ensembles largely reproduce the experimentally measured NOE and 3J-coupling constant data for the three different hepta-beta-peptides, and confirm the relative stabilities of the 3(14)-helical conformation, which is most weakened by substitution of the 4th peptide linkage and least by substitution of the 6th peptide linkage. The simulations are complementary to the experimental data by providing detailed insight into the conformational distributions that are compatible with the experimentally measured average values of observables.

Computational Biology↗

PubMed2006

On using oscillating time-dependent restraints in MD simulation.

The use of time-dependent restraints in molecular simulation in order to generate a conformational ensemble for molecules that is in accordance with measured ensemble averages for particular observable quantities is investigated. Using a model system consisting of liquid butane and the cyclic peptide antamanide the reproduction of particular average (3) J-coupling constant values in a molecular dynamics simulation is analysed. It is shown that the multiple-valuedness and the sizeable gradients of the Karplus curve relating (3) J-coupling constants measured in NMR experiments to the corresponding torsional-angle values cause severe problems when trying to restrain a (3) J-coupling constant to a value close to the extrema of the Karplus curve. The introduction of a factor oscillating with time into the restraining penalty function alleviates this problem and enhances the restrained conformational sampling.

Algorithms↗

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

Molecular dynamics simulations of Hydrogenobacter thermophilus cytochrome c552: comparisons of the wild-type protein, a b-type variant, and the apo state.

Molecular dynamic simulations have been performed for wild-type Hydrogenobacter thermophilus cytochrome c(552), a b-type variant of the protein, and the apo state with the heme prosthetic group removed. In the b-type variant, Cys 10 and Cys 13 were mutated to alanine residues, and so the heme group was no longer covalently bound to the protein. Two 8-ns simulations have been performed for each system at 298 and 360 K. The simulations of the wild-type protein at 298 K show a very close agreement with experimental NMR data. A fluxional process involving the side chain of Met 59, which coordinates to the heme iron, is observed in accord with proposals from NMR studies. Overall, the structure and dynamical behavior of the protein during the simulations of the b-type variant is closely similar to that of the wild-type protein. However, side chains in the heme-binding site show larger fluctuations in the b-type variant simulation at 360 K. In addition, structural changes are seen for a number of residues close to the heme group, particularly Gly 22 and Ser 51. The simulations of the apo state show significant conformational changes for residues 50-59. These residues form a loop region, which packs over the heme group in the wild-type protein and hydrogen bonds to the heme propionate groups. In the absence of heme, in the apo state simulations, these residues form short but persistent regions of beta-sheet secondary structure. These could provide nucleation sites for the conversion to amyloid fibrils.

Alanine↗

PubMed2006

Molecular dynamics study of the stabilities of consensus designed ankyrin repeat proteins.

Two designed ankyrin repeat (AR) proteins (E3_5 and E3_19) are high homologous (with about 87% sequence identity) and their crystal structures have a Calpha atom-positional root-mean-square difference of about 0.14 nm. However, it was found that E3_5 is considerably more stable than E3_19 in guanidinium hydrochloride and thermal denaturation experiments. With the goal of providing insights into the various factors contributing to the stabilities of the designed AR proteins and suggesting possible mutations to enhance their stabilities, homology modeling and molecular dynamics (MD) simulations with explicit solvent have been performed. Because the crystal structure of E3_19 was solved later than that of E3_5, a homology model of E3_19 based on the crystal structure of E3_5 was also used in the simulations. E3_5 shows a very stable trajectory in both crystal and solution simulations. In contrast, the C-terminal repeat of E3_19 unfolds in the simulations starting from either the modeled structure or the crystal structure, although it has a sequence identical to that of E3_5. A continuum electrostatic model was used to estimate the effect of single mutations on protein stability and to study the interaction between the internal ARs and the C-terminal capping AR. Mutations involving charged residues were found to have large effects on stability. Due to the difference in charge distribution in the internal ARs of E3_19 and E3_5, their interaction with the C-terminal capping AR is less favorable in E3_19. The simulation trajectories suggest that the stability of the designed AR proteins can be increased by optimizing the electrostatic interactions within and between the different repeats.

Ankyrin Repeat↗

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

Configurational entropies of lipids in pure and mixed bilayers from atomic-level and coarse-grained molecular dynamics simulations.

Single-chain and single-fragment configurational entropies of lipid tails in hydrated lipid bilayers are evaluated from molecular dynamics simulations using the quasi-harmonic approximation. The entropy distribution along individual acyl tails is obtained and compared to that of corresponding hydrocarbon chains in the liquid phase. We consider pure dipalmitoylphosphatidylcholine and mixed dioleoylphosphatidylcholine/dioleoylphosphatidylethanolamine bilayers. The systems are modeled at different levels of spatial resolution: In an atomic-level (AL) model all (heavy) atoms are explicitly simulated; in a coarse-grained (CG) model particles (beads) representing groups of covalently bound atoms are used, which map approximately four non-hydrogen atoms to one interaction site. Single-chain and single-fragment entropies and correlations between the motions of (single) acyl chains are compared. A good correspondence is found between the flexibility of the AL and CG models. The loss in configurational entropy due to the reduction in the number of degrees of freedom upon coarse-graining of the model is estimated. The CG model shows about 4 times faster convergence of the chain entropies than the more detailed AL model. Corrections to the quasi-harmonic entropy estimates were found to be small for the CG model. For the AL model, the correction due to mode anharmonicities is small, but the correction due to pairwise (supralinear) mode correlations is sizable.

Computer Simulation↗

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

Configurational entropy change of netropsin and distamycin upon DNA minor-groove binding.

Binding of a small molecule to a macromolecular target reduces its conformational freedom, resulting in a negative entropy change that opposes the binding. The goal of this study is to estimate the configurational entropy change of two minor-groove-binding ligands, netropsin and distamycin, upon binding to the DNA duplex d(CGCGAAAAACGCG).d(CGCGTTTTTCGCG). Configurational entropy upper bounds based on 10-ns molecular dynamics simulations of netropsin and distamycin in solution and in complex with DNA in solution were estimated using the covariance matrix of atom-positional fluctuations. The results suggest that netropsin and distamycin lose a significant amount of configurational entropy upon binding to the DNA minor groove. The estimated changes in configurational entropy for netropsin and distamycin are -127 J K(-1) mol(-1) and -104 J K(-1) mol(-1), respectively. Estimates of the configurational entropy contributions of parts of the ligands are presented, showing that the loss of configurational entropy is comparatively more pronounced for the flexible tails than for the relatively rigid central body.

Binding Sites↗

PubMed2006

Comparison of atomic-level and coarse-grained models for liquid hydrocarbons from molecular dynamics configurational entropy estimates.

Molecular liquids can be modeled at different levels of spatial resolution. In atomic-level (AL) models, all (heavy) atoms can be explicitly simulated. In coarse-grained (CG) models, particles (beads) that represent groups of covalently bound atoms are used as elementary units. Ideally, a CG model should reproduce the thermodynamic and structural properties of the corresponding AL model after mapping to the lower-resolution scale. In the present work, two such models are investigated: (i) the classical GROMOS atomic-level model; (ii) a CG model recently proposed by Marrink et al., which maps approximately four non-hydrogen atoms to one bead [J. Phys. Chem. B 2004, 108, 750]. The study is restricted to n-alkanes whose aliphatic fragments are abundantly found in lipids of biological interest. Additionally, cis-9-octadecene is included, as a template chain of the lipid dioleoylphosphatidylcholine (DOPC). The two representations of molecules in the liquid phase are compared in terms of average molecular structures, extent of configurational space sampled, and single-molecule entropies. An approximate method is used to estimate the rotational contributions to the absolute configurational entropy. Good correspondence between the AL and CG representations is found. The loss in configurational entropy due to the reduction in degrees of freedom upon coarse-graining of the model is estimated.

Algorithms↗

PubMed2006

Sampling of rare events using hidden restraints.

A method to enhance sampling of rare events is presented. It makes use of distance or dihedral-angle restraints to overcome an energy barrier separating two metastable states or to stabilize a transition state between the two metastable states. In order not to perturb these metastable end states themselves, a prefactor is introduced into the restraining energy function, which smoothly increases the weight of this function from zero to one at the transition state or on top of the separating energy barrier and then decreases the weight again to zero at the final state. The method is combined with multi-configurational thermodynamic integration and applied to two biomolecular systems, which were difficult to treat using standard thermodynamic integration. As first example the free energy difference of a cyclic alpha-aminoxy-hexapeptide-ion complex upon changing the ion from Cl- to Na+ was calculated. A large conformational rearrangement of the peptide was necessary to accommodate this change. Stabilizing the transition state by (hidden) restraints facilitates that. As a second example, the free energy difference between the 4C1 and the 1C4 conformation of beta-D-glucopyranoside was calculated. In unrestrained simulations the change from the 4C1 into the 1C4 conformation was never observed because of the high energy barrier separating the two states. Using (hidden) restraints, the transition from the 4C1 into the 1C4 state and back could be enforced without perturbing the end states. As comparison, for the same transitions the potential of mean force as obtained by using dihedral-angle constraints is provided.

Journal Article↗

PubMed2006

Multigraining: an algorithm for simultaneous fine-grained and coarse-grained simulation of molecular systems.

A method to combine fine-grained and coarse-grained simulations is presented. The coarse-grained particles are described as virtual particles defined by the underlying fine-grained particles are described as virtual particles defined by the underlying fine-grained particles. The contribution of the two grain levels to the interaction between particles is specified by a grain-level parameter lambda. Setting lambda = 0 results in a completely fine-grained simulation, whereas lambda = 1 yields a simulation governed by the coarse-grained potential energy surface with small contributions to keep the fine-grained covalently bound particles together. Simulations at different lambda values may be coupled using the replica-exchange molecular dynamics method to achieve enhanced sampling at the fine-grained level.

Journal Article↗

PubMed2006

Terminal-group effects on the folding behavior of selected beta-peptides.

It has been suggested that the stability of a beta-peptide helical fold is affected by the interplay between the electrical charge of terminal groups and the dipole due to the helical conformation, the so-called charge-dipole stabilization; the numerical simulations presented herein test that suggestion. The motions of two beta-peptide oligomers, each of which has been shown by NMR spectroscopy to fold into a different helical conformation, have been simulated. The simulated motions bear out empirical observations as to the effect of chemical protection of terminal groups on the stability of beta-peptide helical folds and they support the hypothesis of charge-dipole stabilization.

Computer Simulation↗

PubMed2006

Comparing atomistic simulation data with the NMR experiment: how much can NOEs actually tell us?

Simulated molecular dynamics trajectories of proteins and nucleic acids are often compared with nuclear magnetic resonance (NMR) data for the purposes of assessing the quality of the force field used or, equally important, trying to interpret ambiguous experimental data. In particular, nuclear Overhauser enhancement (NOE) intensities or atom-atom distances derived from them are frequently calculated from the simulated ensembles because the distance restraints derived from NOEs are the key ingredient in NMR-based protein structure determination. In this study, we ask how diverse and nonnative-like an ensemble of structures can be and still match the experimental NOE distance upper bounds well. We present two examples in which simulated ensembles of highly nonnative polypeptide structures (an unfolded state ensemble of the villin headpiece and a high-temperature denatured ensemble of lysozyme) are shown to match fairly well the experimental NOE distance upper bounds from which the corresponding native structures were derived. For example, the unfolded ensemble of villin headpiece, which is on average 0.90 +/- 0.13 nm root-mean-square deviation away from the native NMR structure, deviates from the experimental restraints by only 0.027 nm on average. However, this artificially good agreement is largely a consequence of 1) the highly nonlinear effects of r(-6) (or r(-3)) averaging and 2) focusing only on the experimentally observed set of NOE bounds. Namely, in addition to the experimentally observed NOEs, both simulated ensembles (especially the villin ensemble) also predict a large number of NOEs, which are not seen in the experiment. If these are taken into account, the agreement between simulation and experiment gets markedly worse, as it should, given the nonnative nature of the underlying simulated ensembles. In light of the examples given, we conclude that comparing experimental NOE distance restraints with large simulated ensembles provides just by itself only limited information about the quality of simulation.

Animals↗

PubMed2006

Conformational and dynamical properties of disaccharides in water: a molecular dynamics study.

Explicit-solvent molecular dynamics simulations (50 ns, 300 K) of the eight reducing glucose disaccharides (kojibiose, sophorose, nigerose, laminarabiose, maltose, cellobiose, isomaltose, and gentiobiose) have been carried out using the GROMOS 45A4 force field (including a recently reoptimized carbohydrate parameter set), to investigate and compare their conformational preferences, intramolecular hydrogen-bonding patterns, torsional dynamics, and configurational entropies. The calculated average values of the glycosidic torsional angles agree well with available experimental data, providing validation for the force field and simulation methodology employed in this study. These simulations show in particular that: 1) (1-->6)-linked disaccharides are characterized by an increased flexibility, the absence of any persistent intramolecular hydrogen bond and a significantly higher configurational entropy (compared to the other disaccharides); 2) cellobiose presents a highly persistent interresidue hydrogen bond and a significantly lower configurational entropy (compared to the other disaccharides); 3) persistent hydrogen bonds are observed for all disaccharides (except (1-->6)-linked) and typically involve a hydrogen donor in the reducing residue and an acceptor in the nonreducing one; 4) the probability distributions associated with the glycosidic dihedral angles and psi are essentially unimodal for all disaccharides, and full rotation around these angles occurs at most once or twice for (never for psi) on the 50-ns timescale; and 5) the timescales associated with torsional transitions (except around and psi) range from approximately 30 ps (rotation of hydroxyl groups) to the nanosecond range (rotation of the lactol and hydroxymethyl groups, and around the omega-glycosidic dihedral angle in (1-->6)-linked disaccharides).

Carbohydrate Sequence↗

PubMed2006

Force field evaluation for biomolecular simulation: free enthalpies of solvation of polar and apolar compounds in various solvents.

Recently, the GROMOS biomolecular force field parameter set 53A6--which has been parametrized to reproduce experimentally determined free enthalpies of hydration and solvation in cyclohexane of amino acid side-chain analogs--was presented. To investigate the transferability of the new parameter set, we calculated free enthalpies of solvation of a range of polar and apolar compounds in different solvents (methanol, dimethyl sulfoxide (DMSO), acetonitrile, and acetone) from molecular dynamics simulations using the GROMOS 53A6 force field. For methanol and DMSO, parameters were used that are available in the 53A6 parameter set. For acetonitrile, a recently developed model was taken and for acetone, two models available in literature were used. We found that trends in and values for the solvation free enthalpies are in satisfactory agreement with experiment, except for the solvation in acetone for which deviations from experiment can be explained in terms of the properties of the models used.

Amino Acids↗