Terry P. Lybrand

Ionic Association in Water: From Atoms to Enzymesa

Chemistry and biochemistry are largely concerned with the association and transformation of molecules in water. Theoretical studies of such processes have in the past been hindered by a number of difficulties. Within an aqueous system, there are strong, directional, attractive forces among the water molecules, and often also between solute and solvent molecules, in addition to the excluded volume forces that have made even simple liquids a challenging subject.s2 For a model system comprising a few solute molecules and a few hundred water molecules, the competition among these interactions produces a complicated potential energy surface with many local minima. To calculate structural or thermodynamic properties, one must evaluate averages of certain quantities over a representative set of those configurations that have low enough energy to be thermally populated. To calculate kinetic properties, one must consider motions over energy barriers and, in the case of molecular association, motions corresponding to large displacements over the potential surface. From the perspective of computer simulations, the difficulties that arise in any of the calculations mentioned above are largely associated with the time scales involved. In conventional molecular dynamics simulations, where one solves Newtons equations for the atoms in a model system, the accessible times on conventional computers have been too short for brute-force simulation of many systems. For example, a simulation to generate a fairly representative set of instantaneous hydration structures of a small univalent ion might involve about two hundred molecules and 20 psec of simulation; this would require about 60 hours of CPU time on a VAX 11/780; this is quite manageable. To study the hydration of a moderately large enzyme such as trypsin, however, a 20-psec simulation might require 3500 hrs on a VAX; this is cumbersome a t best. For kinetic properties such as rate constants for barrier crossing or diffusional encounter, the situation can be worse by many orders of magnitude. Happily, advances in the theory underlying computer simulations, in the algorithms used, and in computers themselves, have greatly expanded the range of

Molecular Dynamics of Coat Proteins of the Human Rhinovirus

Abstract The effects of the oxazole antiviral WIN 52084 on the thermal vibrations of the coat proteins of the human rhinovirus were studied by means of a comparison of two molecular dynamics simulations. One simulation involved only a protomeric unit (cluster of four proteins) of the viral coat, while the other included the antiviral drug bound to the protein cluster. Analysis of the RMS fluctations for all atoms indicates that the drug did not cause any statistically significant global changes in the amplitude of atomic motion. However, the RMS fluctuation of seventeen residues in the vicinity of the drug decreased by about 11%. Two global effects were observed. Most importantly, the drug was found to make the decay times of the atomic fluctuations more uniform. Also, the drug lowered the average correlation time for displacements of atoms in the drug-bound cluster. Finally, a comparison of the differences in the normalized cross-correlation functions of residues close to the binding site showed that the...

Protein Stability and Function

The convergence of several lines of development in chemistry and molecular biology has created major new needs and opportunities for theoretical studies of proteins. The traditional approaches of organic synthesis have been supplemented by methods for automated chemical synthesis and genetic engineering that allow the preparation of a wide variety of polypeptides, specifically altered enzymes, and other complex molecules. The choice of molecules to be synthesis for a given application is increasingly guided by structural information in addition to traditional methods such as chemical intuition and empirical correlation (quantitative structure-activity relationships, or QSAR). X-ray area detectors and new methods in NMR spectroscopy, combined with the improvements in our ability to synthesize and purify samples, are increasingly the rate at which high-resolution structures to proteins are becoming available.

Polarizable water models: Vectorization of energy calculations on the CYBER 205

Abstract A large fraction of the time spent calculating the energy of a configuration of polarizable water molecules is spent calculating the electric field and polarization energy. This paper describes vectorization strategies for such calculations on the CYBER 205. For a cluster of 215 waters and the Lybrand-Kollman model, the vectorized calculation on the CYBER 205 executes at about 47 times VAX 8650 speed, or about 300 times VAX 11/780 speed.