Simulation of Protein and Hydride Transfer in Enzymes

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DESCRIPTION (provided by applicant): The broad, long-term objectives of this research are to elucidate the fundamental principles and mechanisms of hydrogen transfer in enzyme catalysis and to address unresolved issues in biologically important systems. These objectives will be accomplished with a recently developed mixed quantum-classical molecular dynamics approach that includes electronic and nuclear quantum effects, as well as the motion of the entire solvated enzyme. The first specific aim is to determine the impact of enzyme structure and motion on catalysis. The second specific aim is to clarify the role of nuclear quantum effects such as zero point motion and hydrogen tunneling in enzyme catalysis. The remaining three specific aims address these issues for three enzyme reactions, which have been chosen on the basis of their biomedical importance and the availability of relevant experimental data. The third specific aim centers on the enzyme dihydrofolate reductase (DHFR), which is required for normal folate metabolism in prokaryotes and eukaryotes. This enzyme is essential for the maintenance of tetrahydrofolate levels required to support the biosynthesis of purines, pyrimidines, and amino acids. DHFR is medically relevant, in that inhibition of DHFR with potent antifolates has been used successfully in cancer chemotherapy. The fourth specific aim centers on the enzyme dihydroorotate dehydrogenase (DHOD). This enzyme catalyzes the only redox reaction in the biosynthesis of pyrimidines, which are required for the supply of precursors for RNA and DNA synthesis. DHOD is medically relevant, in that the immunosuppressive effects of inhibiting this enzyme have been used therapeutically. The fifth specific aim centers on lipoxygenase, which serves numerous vital roles in plants and mammals. In mammals, lipoxygenases are medically relevant, in that they mediate processes such as asthma, atherosclerosis, psoriasis, inflammatory diseases, and cancer growth.