Protein dynamics are known to be essential during enzyme catalysis. However, a precise molecular understanding of these dynamics is currently lacking. Such a picture would assist in understanding why and how particular proteins catalyze particular reactions. This would be useful in designing new drugs to inhibit specific enzymatic reactions as well as in designing new proteins to have better catalytic properties than naturally occurring proteins. The ultimate objective of this research, which this fellowship would support, is to understand the interaction between dynamics and catalysis in biological systems. Computational and theoretical methodology will be further developed to explore this interaction and the methodology will be applied ti biologically significant systems to obtain detailed molecular pictures of their activities. In particular, the systems studies will be dihydrofolate reductase (DHFR) and metallo-b-lactamase. The former is important in maintaining intracellular pools of THF which are used in biosynthesis. The later enzyme is implicated in bacterial drug resistance. So a detailed understanding of the catalytic cycles of these systems could assist in drug design. This applicant's role will be to further develop the theoretical and computational methodology. The theoretical investigations will be performed in close collaboration with the NMR groups of Wright and Dyson who will be conducting experimental studies of the same systems.
