THEORY AND MODELING OF NONCOVALENT BINDING

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DESCRIPTION: The noncovalent association of molecules in solution is of fundamental importance in biology and medicine. In particular, many medications work by binding to specific protein targets. For example, an important class of AIDS medications works by binding to and inhibiting the function of HIV-1 protease, an enzyme that is essential for the growth of the AIDS virus. Thus, research projects aimed at developing new medications often center around the discovery of molecules that bind a targeted protein. The present project seeks to develop theory and methods that will facilitate this step in drug-design, by developing a better understanding of the physical mechanisms of noncovalent binding, and by creating algorithms and computer programs that can be used to predict what molecules will bind to a selected molecular target. The specific aims of this project include elucidation of the theory connecting molecular simulations with measured binding affinities; further development of a promising new class of algorithms for computing binding free energies; analysis and improvement of efficient models of the solvent for use in binding calculations; and validation of the new models against experimental data.