The research program centers on the development and use of computational methods to make quantitative predictions on the structure, energetics, and reactivity of biomolecular systems. Such work promotes the deeper understanding of biochemical structure and function and the improvement of predictive skills of importance in many areas including the rational design of therapeutic drugs. The theoretical approach features computer simulations at the atomic level with explicit inclusion of the solvent. The principal techniques are quantum mechanics and Monte Carlo (MC) statistical mechanics with emphasis on computing changes in free energy for transformations in solution. The proposed research includes the development of force fields and modeling software with application directed at protein-ligand binding, inhibitor design, and the elucidation of enzyme mechanisms. Effort will be directed specifically at (1) expansion of the OPLS all-atom force field with parallel development of the polarizable force field, OPLS-POL, (2) extensive studies of protein-ligand complexes, e.g., for thrombin and Src SH2 domain, aimed both at in-depth understanding of variations in binding affinities and at participating in the design of inhibitors with therapeutic potential for combating coronary diseases, cancer, and osteoporosis, (3) development of a protein-ligand docking program for drug lead discovery, and (4) application of mixed quantum and molecular mechanics (QM/MM) calculations to study enzymatic reactions; a detailed reaction pathway is sought for the hallmark enzymatic cyclization of squalene to the steroid hopene, and additional work will address the covalent inhibition of human rhinovirus 3C protease.
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