The long term objectives of the research described in this proposal involve understanding the structure and function of proteins at the detailed molecular level. The specific goals are to achieve a qualitative understanding of the role of electrostatic interactions in proteins and to develop theoretical and computational tools which allow an accurate quantitative treatment. In the past few years it has become possible to calculate electrostatic interactions by combining a continuum treatment of solvent with a microscopic atomic-level description of the protein. The entire system is mapped onto a three-dimensional lattice and a finite difference algorithm is then used to solve the Poisson-Boltzmann equation (the FDPB method). There are two major sections in this proposal. The first involves applications of the FDBP method to a variety of problems in protein structure and function. These include electrostatic effects on protein stability, the calculation of pKs of ionizable groups, determining the factors that control calcium binding and specificity and understanding the energetics of protein-protein interactions. The second section involves studies aimed at improving the theoretical understanding and computation tools necessary for a reliable treatment of electrostatic interactions. The plans include both FDBP and free energy simulations of charge-charge interactions and solvation energies in model systems and the development of new techniques to account for the important effects of electronic polarization in energy calculations. The health relatedness of the research is in the potential it offers for an improved understanding of protein structure and function and, more specifically, in the insights and methodology it will provide for rational drug design. Moreover, the results from our proposed studies of aspartyl proteases should be useful in the design of inhibitors to renin and to the aspartyl protease of HIV.
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