Roger Abseher

The influence of a protein on water dynamics in its vicinity investigated by molecular dynamics simulation

A system containing the globular protein ubiquitin and 4,197 water molecules has been used for the analysis of the influence exerted by a protein on solvent dynamics in its vicinity. Using Voronoi polyhedra, the solvent has been divided into three subsets, i.e., the first and second hydration shell, and the remaining bulk, which is hardly affected by the protein. Translational motion in the first shell is retarded by a factor of 3 in comparison to bulk. Several molecules in the first shell do not reach the diffusive regime within 100 ps. Shell‐averaged orientational autocorrelation functions, which are also subject to a retardation effect, cannot be modeled by a single exponential time law, but are instead well‐described by a Kohlrausch‐Williams‐Watts (KWW) function. The underlying distribution of single‐molecule rotational correlation times is both obtained directly from the simulation and derived theoretically. The temperature dependence of reorientation is characterized by a strongly varying correlation time, but a virtually temperature‐independent KWW exponent. Thus, the coupling of water structure relaxation with the respective environment, which is characteristic of each solvation shell, is hardly affected by temperature. In other words, the functional form of the distributions of single‐molecule rotational correlation times is not subject to a temperature effect. On average, a correlation between reorientation and lifetimes of neighborhood relations is observed.

The influence of temperature on pairwise hydrophobic interactions of methane‐like particles: A molecular dynamics study of free energy

The association of a pair of hydrophobic solutes in water has been investigated by free energy molecular dynamics simulations of a system containing 516 water molecules. Convergence of the calculations is guaranteed by the comparison of data obtained with two independent free energy sampling techniques, which have been optimized for our system. Coulomb interactions have been treated with the Ewald method. Using this computationally expensive approach many of the previously reported discrepancies in the temperature, pressure and interaction parameter dependence of hydrophobic association are clarified. A temperature effect on both the free energy of association and the equilibrium between contact and solvent‐separated species is observed. Raising temperature favors association. The most pronounced temperature dependence occurs in the interval between 300 and 350K.

Essential spaces defined by NMR structure ensembles and molecular dynamics simulation show significant overlap

Large concerted motions of proteins which span its “essential space,” are an important component of protein dynamics. We investigate to what extent structure ensembles generated with standard structure calculation techniques such as simulated annealing can capture these motions by comparing them to long‐time molecular dynamics (MD) trajectories. The motions are analyzed by principal component analysis and compared using inner products of eigenvectors of the respective covariance matrices. Two very different systems are studied, the β‐spectrin PH domain and the single‐stranded DNA binding protein (ssDBP) from the filamentous phage Pf3. A comparison of the ensembles from NMR and MD shows significant overlap of the essential spaces, which in the case of ssDBP is extraordinarily high. The influence of variations in the specifications of distance restraints is investigated. We also study the influence of the selection criterion for the final structure ensemble on the definition of mobility. The results suggest a modified criterion that improves conformational sampling in terms of amplitudes of correlated motion. Proteins 31:370–382, 1998.

Efficient Sampling in Collective Coordinate Space

Collective motions in biological macromolecules have been shown to be important for function. The most important collective motions occur on slow time scales, which poses a sampling problem in dynamic simulation of biomolecules. We present a novel method for efficient conformational sampling. The method combines the simulation of an ensemble of concurrent trajectories with restraints acting on the ensemble of structures as a whole. Two properties of the ensemble may be restrained: (i) the variance of the ensemble and (ii) the average position of the ensemble. Both properties are defined in a subspace of collective coordinate space spanned by an arbitrary number of modes. We show that weak restraints on the ensemble variance suffice for an increase in sampling efficiency along soft modes by two orders of magnitudes. The resulting trajectories exhibit virtually the same structural quality as trajectories generated by restraint‐free‐molecular dynamics simulation, as judged by standard structure validation tools. The method is used to probe the resistance of a structure against conformational changes along collective modes and clearly distinguishes soft from stiff modes. Further applications are discussed. Proteins 2000;39:82–88.