Our proposed studies aim to continue development of the 1-dynamics methodology to free energy-based calculations of ligand-protein interactions. Specifically, (i) we will extend and develop the 1- dynamics approach for screening of multiple ligands in a common receptor. Furthermore (ii) we will develop new methods to permit """"""""combinatorial"""""""" searches through chemical functional groups at multiple sites of diversity on a common framework bound in a common receptor, thereby implementing a free energy-based """"""""combinatorial library"""""""" assessment screen. Testing of these methods will be carried out on a series of heterocyclic ligands that bind to an engineered cavity in cytochrome c peroxidase (CCP). We will utilize the extensive database of compounds bound to the mutant W191G mutant CCP, for which Goodin and his colleagues have characterized both structure and binding thermodynamics. New methods to explore the development of starting structures for ligands bound to proteins will also be emphasized. Our approaches to """"""""ligand-docking"""""""" will exploit preliminary studies which systematically explore energy functions and docking protocols on a test set of five known ligand-receptor complexes with varying complexity. Finally, applications of these methods, both docking and free energy simulations will be made in two main areas. The first involves the role of electrostatic interactions in stabilizing heterocyclic ring systems in the cavity engineered into CCP. In collaboration with D. Goodin and his group, we will explore the requirements for strong ligand binding and attempt design of ligands that permit oxidative chemistry to take place on such ligands. A second area of investigation will exploit ongoing studies of our colleagues, Wong and Elder, to examine the thermodynamic and structural requirements for the development of HIV protease inhibitors that show """"""""resistance to resistance"""""""". We will utilize structural and thermodynamic studies on proteases from HIV and FIV as starting points for free energy based modeling of interactions in these systems.
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