The long range goal of this project is to develop and apply theoretical computer simulation methods to enable an accurate prediction of the structures and interaction free energies of small molecules with proteins and the activation free energies of enzyme catalyzed reactions. Such a predictive model would enable one to design selective and effective inhibitors for enzymes and to design more effective enzyme catalysts. The ability to design effective enzyme inhibitors would have enormous implications for human health and the design of enzyme catalysts would be very useful in biotechnological applications. To reach the long range goal, studies are proposed to develop efficient strategies for conformational analysis of molecules, to more accurately represent the energies of molecular interactions, to develop methods to calculate energy differences between related systems and to more effectively couple quantum mechanical and molecular mechanical/dynamical methods. These methods will be developed and tested on a variety of protein systems, i.e., the serine and cysteine protease hydrolytic enzymes, enzymes which interact with highly changed substrates such as triose phosphate isomerase, adenylate kinase and staphloccocal nuclease, trp repressor protein and T4 lyzozyme. The specific objectives in the studies on these proteins include the elucidation of the complete free energy profile for enzyme catalysis (serine proteases and cysteine proteases) and comparable biomimetic and non-catalyzed reaction profiles, which should lead to an understanding of what makes enzyme catalysis unique; secondly, simulations to understand protein conformational changes (adenylate kinase and trp repressor) in terms of the molecular forces of the system; and finally, the development of methods to simulate and understand the principles in and design of thermally more stable proteins (myoglobin and T4 lyzozyme).
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