The research program centers on the development and use of computational methods to make quantitative predictions on the structure, energetics, and reactivity of proteins. Progress in this field is essential for the deeper understanding of biochemical structure and function, and for the improvement of predictive skills of importance, for example, in the design of therapeutic drugs. The theoretical approach features computer simulations at the atomic level with explicit inclusion of the solvent. The principal techniques are Monte Carlo (MC) statistical mechanics and molecular dynamics (MD) with emphasis on computing changes in free energy for transformations in solution. The proposed research includes the development of force field and modeling software with applications concerning protein-ligand binding inhibitor design, protein stability, and pathways of protein denaturation. Effort will be directed specifically at (1) completion of the all-atom OPLS force field, followed by pursuit of the next generation of force field incorporating explicit polarization, (2) refinement of the MCPRO program for MC simulations of proteins as an alternative to MD, especially for free energy calculations, (3) extensive studies of protein-ligand complexes, e.g., for thrombin and Src homology domains, aimed both at in- depth understanding of variations in binding affinities and at participating in the design of enzyme inhibitors with therapeutic potential for coronary diseases, immune system regulation, and hyperproliferative disorders including cancer and allergies, (4) investigation of factors controlling protein stability such as the propensities for the different amino acids to occur on central or edge strands of beta sheets, (5) gaining insights into protein folding/ unfolding through further MD simulations of protein denaturation including for barnase at different temperatures and in the presence or absence of urea, and (6) elucidation of the origin of the effects of 2,2,2- trifluoroethanol (TFE) on helicity.
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