The long term objectives of this work are (a) the development of theoretical methods for the quantitative description of bimolecular diffusional phenomena such as the binding of ligands to receptors, and of unimolecular diffusional phenomena such as the transport and certain conformational transitions of molecules and molecular assemblies; and (b) the application of these methods to interpret experimental data (e.g., spectroscopic, kinetic, transport), provide mechanistic pictures, and design functional modifications for specific biological molecules. Concerning (a), statistical mechanics will be used to provide more realistic and accurate descriptions of the effective forces between molecules in electrolyte solutions and to characterize the effects of intramolecular dynamics on molecular reactivity. Also, theoretical and computational studies will be pursued to improve the efficiency of the Brownian dynamics computer simulations that are used to study particular model systems. Concerning (b), simulation methods will be used to provide accurate rate constants for catalysis by the enzyme, superoxide dismutase, in both native and chemically or genetically altered forms; and to determine the rate of ligand binding to an antibody, to the enzyme lysozyme, and to cytochrome c. The dynamics of helix-coil transitions will be determined for polypeptides interacting with binding surfaces, and the conformational dynamics and transport of antibody molecules will be characterized. Specific health relatedness arises from the possible utility of superoxide dismutase to prevent tissue damage during reperfusion of coronary or renal blood vessels; the role of helix induction in the binding of glucagon and other hormones and peptide ligands; the utility of the theoretical methods in characterizing details of the function of antibodies, enzymes, and other biological molecules; and the potential utility of these methods as tools for bimolecular design.
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