. This research is intended to increase our understanding of diffusion-controlled processes in biology. More precisely, theoretical and computational work will be done to provide increasingly detailed and accurate analyses of the rates of diffusion-controlled enzymatic reactions. A few selected biomolecular systems will be studied in great depth. This approach should facilitate the discovery of concepts of broad relevance in addition to clarifying the mechanisms of the particular systems chosen for study. Comparisons will be made to experimental data obtained under a variety of conditions, both to test the theoretical models and to aid in the interpretation of the experiments. Other parts of the proposed work involve the development of tools for diffusional simulations and, secondarily, for the calculation of electrostatic forces, which are of special importance in influencing biomolecular diffusion. Among the specific questions that this project will seek to answer are the following. How do the effects of modifications at different sites combine to produce changes in the catalytic rate of Cu, Zn superoxide dismutase (SOD)? How can simulations of the diffusional encounter of substrate with the surface of SOD be combined with detailed simulations of subsequent events to provide a more complete description of SOD activity? Can the tools developed in this work be extended to enzymes such as Mn SOD and triose phosphate isomerase (TIM), where successively larger motions in the enzyme may modulate substrate access to the active site? The health relatedness of this work is in the tools it should yield for the rational design of molecules with desired kinetic properties. E.G., SOD is being considered for pharmacologic use; the methods developed in this work could help in engineering SOD to increase its diffusion-controlled rate of action.
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