Obtaining a quantitative description of enzyme catalysis is one of the most fundamental problems in molecular biology. Dr. Warshel proposes a continuation of his long-term research project, aimed at the development, improvement and validation of computational models for quantitative structure-catalysis correlation of enzyme-substrate complexes, and for computer-aided elucidation of mechanisms of enzymatic reactions. In the previous grant period, Dr. Warshel continued to use his Empirical Valence Bond (EVB) method in studies of enzymatic reactions. He also augmented this approach with several ab initio strategies, including the development of an ab initio/Free Energy Perturbation (QM/(ai)/FEP) approach and the Frozen Density Functional Theory (FDFT) approach, as well as the implementation of an efficient ab initio/Langevin dipoles approach. These methods have provided very encouraging results in preliminary studies of chemical reactions and also to use them as a systematic tool for refining EVB potential surfaces of enzymatic reactions. In addition to developing and refining simulation approaches, Dr. Warshel intends to progress aggressively in studies of major classes of enzymatic reactions, and in fundamental studies of general aspects of enzyme catalysis and related biological processes. His main proposed studies include the following projects: (i) Implementation of the ab initio/FEP approach in simulations of enzymatic reactions and in refinement and validation of the corresponding EVB results; (ii) Using the FDFT approach in studies of metalloenzymes; (iii) Examination of the performance of the ab initio/Langevin dipoles approach in studies of enzymatic reactions; (iv) Extensive studies of specific classes of enzymes. These will include studies of DNA polymerases, carbonic anhydrase, and various proteases; (v) Studies of entropic effects in enzymes catalysis; (vi) Examination of his ability to combine the information from experiment and simulations in determining whether an enzymatic reaction involves a concerted or stepwise mechanism; (vii) Continuation of his studies of electrostatic effects in macromolecules.
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