Completeness in structural genomics.

Structural genomics has the goal of obtaining useful, three-dimensional models of all proteins by a combination of experimental structure determination and comparative model building. We evaluate different strategies for optimizing information return on effort. The strategy that maximizes structural coverage requires about seven times fewer structure determinations compared with the strategy in which targets are selected at random. With a choice of reasonable model quality and the goal of 90% coverage, we extrapolate the estimate of the total effort of structural genomics. It would take approximately 16,000 carefully selected structure determinations to construct useful atomic models for the vast majority of all proteins. In practice, unless there is global coordination of target selection, the total effort will likely increase by a factor of three. The task can be accomplished within a decade provided that selection of targets is highly coordinated and significant funding is available.

Solvent mobility and the protein 'glass' transition.

Proteins and other biomolecules undergo a dynamic transition near 200 K to a glass-like solid state with small atomic fluctuations. This dynamic transition can inhibit biological function. To provide a deeper understanding of the relative importance of solvent mobility and the intrinsic protein energy surface in the transition, a novel molecular dynamics simulation procedure with the protein and solvent at different temperatures has been used. Solvent mobility is shown to be the dominant factor in determining the atomic fluctuations above 180 K, although intrinsic protein effects become important at lower temperatures. The simulations thus complement experimental studies by demonstrating the essential role of solvent in controlling functionally important protein fluctuations.

Native proteins are surface-molten solids: application of the Lindemann criterion for the solid versus liquid state.

Since the internal motions of proteins play an essential role in their biological function, it is important to characterize them in a fundamental way. The Lindemann criterion for the solid state is applied to molecular dynamics simulations and temperature-dependent X-ray diffraction data of proteins. It is found that the interior of native proteins is solid-like, while their surface is liquid-like. When the entire protein becomes solid-like at low temperature ( approximately 220 K), the protein is inactive. Thus, the surface-molten solid nature of proteins in their native state permits the dynamics required for function, while preserving their stability. Comparison with rare gas clusters and polymer models indicates that their thermodynamic phase diagrams have many elements in common with those of proteins.

A comparison between molecular dynamics and X-ray results for dissociated CO in myoglobin.

The distribution of carbon monoxide after photodissociation in the myoglobin haem pocket has been investigated using molecular dynamics simulations at 300 K. The results show that both intermediates (one close to the haem iron and one further away) observed in recent low temperature X-ray studies of photodissociated CO have a high probability of occurrence, even at ambient temperatures. The fact that the O of CO is oriented toward the haem iron in the closer intermediate provides an explanation for the slow rate of CO geminate rebinding. A refinement against X-ray data generated from the molecular dynamics simulations indicates that the CO has a broader distribution in the haem pocket than is apparent from the experimental electron density. This effect is likely to be general for systems containing highly mobile groups.