Residence times of water molecules in the hydration sites of myoglobin.

Hydration sites are high-density regions in the three-dimensional time-averaged solvent structure in molecular dynamics simulations and diffraction experiments. In a simulation of sperm whale myoglobin, we found 294 such high-density regions. Their positions appear to agree reasonably well with the distributions of waters of hydration found in 38 x-ray and 1 neutron high-resolution structures of this protein. The hydration sites are characterized by an average occupancy and a combination of residence time parameters designed to approximate a distribution of residence times. It appears that although the occupancy and residence times of the majority of sites are rather bulk-like, the residence time distribution is shifted toward the longer components, relative to bulk. The sites with particularly long residence times are located only in the cavities and clefts of the protein. This indicates that other factors, such as hydrogen bonds and hydrophobicity of underlying protein residues, play a lesser role in determining the residence times of the longest-lived sites.

Diffusion of solvent around biomolecular solutes: a molecular dynamics simulation study.

Effects of the macromolecular solute on the translational mobility of surrounding solvent water, and Na+ and Cl- ions are investigated by molecular dynamics (MD) simulation. Using MD trajectories of myoglobin and d(C5T5) . d(G5A5) DNA decamer of high quality and length, we determine the average diffusion coefficients for all solvent species as a function of distance from the closest solute atom. We examine solvent mobility in the directions parallel and perpendicular to the solute surface and in proximity to three different classes of solute atoms (oxygens, nitrogens, and carbons). The nature and the magnitude of the solute effects on water diffusion appear to be very similar for protein and DNA decamer. The overall diffusion rate at the interface is lower than in the bulk. The rate is higher than the average in the direction parallel to the solute surface, and lower in the direction normal to the surface, up to 15 A away from the solute. The rate is also lower in the solvation shells of the macromolecules, producing characteristic depressions in the radial profiles of the diffusion coefficient that can be correlated with peaks in the corresponding radial distribution functions. The magnitude of these depressions is small compared to the overall change in solvent mobility at the interface. Similar features are observed in the radial profiles of the diffusion coefficient of sodium and chlorine ions as well.

Characterizing global substates of myoglobin.

BACKGROUND: The massive amount of information generated from current molecular dynamics simulations makes the data difficult to analyze efficiently. Principal component analysis has been used for almost a century to detect and characterize data relationships and to reduce the dimensionality for problems in many fields. Here, we present an adaptation of principal component analysis using a partial singular value decomposition (SVD) for investigating both the localized and global motions of macromolecules. RESULTS: Configuration space projections from the SVD analysis of a variety of myoglobin simulations are used to characterize the dynamics of the protein. This technique reveals new dynamical motifs, which quantify proposed hierarchical structures of conformational substates for proteins and provide a means by which configuration space sampling efficiency may be probed. The SVD clearly shows that solvent effects facilitate transitions between global conformational substates for myoglobin molecular dynamics simulations. Lyapunov exponents calculated from the configuration space divergence of 15 trajectories agree with previous predictions for the chaotic behavior of complex protein systems. CONCLUSIONS: Configuration space projections provide invaluable information about protein motions that would be extremely difficult to obtain otherwise. While the configuration space for myoglobin is quite large, it does have structure. Our analysis of this structure shows that the protein hops between a number of distinct global conformational states, much like the local behavior observed for an individual residue.

Protein hydration density: theory, simulations and crystallography.

Models of protein hydration are becoming increasingly more accurate in comparison with experimental data. The recent success of these models implies that the major features of the solvation layers are dominated by local correlations and that such correlations are universal. The excellent agreement between theoretical and experimental solvent electron density radial distributions marks a significant success in our ability to accurately model macromolecular hydration.

Reconstructing the protein-water interface.

Using molecular dynamics simulations of fully hydrated proteins and analysis of crystal structures contained in the Protein Data Bank, we develop a transferable set of perpendicular radial distribution functions for water molecules around globular proteins. These universal functions may be used to reconstruct the unique three-dimensional solvent density distribution around every individual protein with a modest error. We discuss potential applications of this solvent treatment in protein x-ray crystallographic refinements and in theoretical modeling. We also present a fast, grid-based algorithm for construction of the perpendicular solvent density distributions.

A sampling problem in molecular dynamics simulations of macromolecules.

Correlations in low-frequency atomic displacements predicted by molecular dynamics simulations on the order of 1 ns are undersampled for the time scales currently accessible by the technique. This is shown with three different representations of the fluctuations in a macromolecule: the reciprocal space of crystallography using diffuse x-ray scattering data, real three-dimensional Cartesian space using covariance matrices of the atomic displacements, and the 3N-dimensional configuration space of the protein using dimensionally reduced projections to visualize the extent to which phase space is sampled.