Chung F. Wong

Glass transition in SPC/E water and in a protein solution: A molecular dynamics simulation study

Abstract Molecular dynamic simulations of glass transitions in SPC/E water and tuna ferrocytochrome c solution have been performed. The results support the suggestion that glass transitions in proteins are driven by those in the surrounding solvent.

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

Quantum simulation of ferrocytochrome c.

The dramatic progress in the understanding of the dynamics of biomolecules has been largely fuelled by computer simulations based on the law of classical mechanics1. However in some respects biomolecules are at the borders of the domain of applicability of classical mechanics. The role of quantum mechanical effects in biomolecular structure and function is therefore worth investigating. Here we present preliminary results from a quantum simulation of a protein and contrast them with results from full classical simulations. The most significant differences are found in motions of high frequency, such as bond stretching or the torsional oscillation of groups that bear hydrogen atoms. The amplitudes of such motions are significantly increased by the penetration of atoms into classically forbidden regions. These differences will directly influence the rates of such processes as proton and electron transfer.

Thermodynamics of Enzyme Folding and Activity: Theory and Experiment

The thermodynamic cycle--perturbation method is a new theoretical approach for predicting how alterations in molecular structure will change the thermodynamics of any of a large number of possible molecular processes (1–7). The structural alteration might for example be a single-site mutation in a protein or a chemical modification of a drug molecule. The process of interest might be the folding of a protein, the binding of a ligand to a receptor, the association of a repressor protein to an operator region of DNA, etc.; and the thermodynamic quantity to be predicted might be a relative free energy of folding or binding, an entropy or enthalpy of activation, or any other quantity.

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.

Molecular dynamics simulation of protein hydration: Studies on tuna ferrocytochrome-c and bovine erythrocyte superoxide dismutase

Abstract Some results obtained from recent molecular dynamics simulations of tuna ferrocytochrome-c and bovine erythrocyte superoxide dismutase in water are reviewed. The simulation of cytochrome-c shows that the amplitudes of fluctuation of the protein atoms are similar to those obtained from a previous simulation in which the solvent was represented implicitly. The radial dependence of mobility of water around cytochrome-c exhibits a maximum at about 2 nm from the protein center of mass, similar to a previous simulation of trypsin in water. The simulation of bovine erythrocyte superoxide dismutase shows that the fluctuation of the channel to the active site is rather large, which may be important in allowing superoxide to diffuse to that site. The water structure in the channel is rather pronounced and may modulate the electrostatic environment around the active site and influence the diffusional encounter of superoxide with the enzyme.