Computational Methods for Determining Binding Free Energies

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The major component of the proposal is the development of methods designed to substantially increase the range of biomolecular systems to which advanced computational docking and design methodologies can be applied. The most successful methods and applications to date have been limited to proteins whose crystal structures are known, and which remain relatively rigid during complex formation. The main obstacle limiting the analysis of more general systems in which side chains and backbones change conformation is the target function. The proposal therefore focuses on methods for obtaining accurate, rapidly evaluatable semi-empirical free energy functions, with particular emphasis on solvation. These include methods for eliminating the time intensive surface area calculations required by current semi-empirical free energy functions, as well as several new approaches to solvation. Docking algorithms that can take full advantage of free energy- target functions will also be developed and tested in a variety of applications, exploiting the extensive crystallographic and thermodynamic databases available. Attention will be given to the systematic comparison of currently available and emerging semi-empirical free energy evaluation procedures, including the delineation of their range of applicability. J