Application of Molecular Dynamics Simulations to Conformational Stability of Peptides and Proteins

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9314854 Hermans This study will investigate the equilibria involved in the initiation and growth of alpha-and 310 helices, of turns and of beta strands and the differences in propensity towards formation these structures for different amino acid types. These methods will also be applied to simulation of the activities and inhibition of two enzymes, cytidine deaminase and cyclophilin. The proline isomerase activity of cyclophilin is thought to involve the catalysis of a conformation change, without formation of breaking of a chemical bond. Catalysis by cytidine deaminase appears to require significant conformation change to admit substrate and expel product. Several components of the project will be directed at development or improvement of techniques that may have general applicability. Development of a method (based on work published by Friedman in 1975) to do molecular dynamics simulations of proteins in a spherical "bath" filled with explicit water molecules, with a so-called reaction field that accounts for the presence of a medium with high dielectric constant (water) on the outside, even though no molecules are explicitly represented there. If this implementation is successful, then it will be combined with the fast multipole method (Greengard; Board) for calculation of all long-range electrostatic forces. Other proposed new developments include an improved method for the calculation of absolute binding free energies and the implementation of molecular dynamics programs on parallel machines with many processors. %%% Hardly a single processes involving the action of a protein does not involve a conformation change of some kind, and is fully understood without an understanding of the nature of conformation change. The very process of formation of native protein molecules from an unordered state is a process of coupled and sequential conformation changes that is not at all well understood, and conformation change is critical in the action of nearly all enzymes. This project will apply accurate computer simulation methods to the study of conformation change of peptides and proteins. Molecular dynamics simulations and specialized versions thereof, capable of calculation of free energy differences will be used with a variety of problems. In earlier work the focus of this project has been on validation of the method by application to problems for which precise experimental results are available. This will continue, but increasingly the project will include to problems where experiments have given little or no information about conformational equilibria. %%%