SCIENCE AT THE EDGE SEMINAR Friday, October 6 at 11:30am Room 1400 Biomedical and Physical Sciences Bldg. Refreshments at 11:15 Speaker: Sharon Hammes-Schiffer Department of Chemistry Pennsylvania State University, University Park, PA 16802 Title: Hydrogen Tunneling and Protein Motion in Enzyme Reactions Abstract: Theoretical studies of proton, hydride, and proton-coupled electron transfer reactions in enzymes will be presented. We have developed a theoretical formulation for proton-coupled electron transfer reactions. The quantum mechanical effects of the active electrons, transferring proton, and donor-acceptor mode are included in this formulation, and analytical nonadiabatic rate expressions have been derived in various limits. The application of this approach to proton-coupled electron transfer in the enzyme lipoxygenase will be discussed. The experimentally measured deuterium kinetic isotope effect of 80 at room temperature is found to arise from the small overlap of the reactant and product proton vibrational wavefunctions. Our calculations illustrate that the proton donor-acceptor vibrational motion plays a vital role in the proton-coupled electron transfer reaction. We have also developed a hybrid quantum/classical molecular dynamics approach that includes electronic and nuclear quantum effects, as well as the motion of the entire solvated enzyme. The application of this approach to hydride transfer in the enzyme dihydrofolate reductase will be discussed. An analysis of the simulations leads to the identification and characterization of a network of coupled motions that extends throughout the enzyme and represents conformational changes that facilitate the charge transfer process. Mutations distal to the active site are shown to significantly impact the catalytic rate by altering the conformational motions of the entire enzyme and thereby changing the probability of sampling conformations conducive to the catalyzed reaction. References: E. Hatcher, A. V. Soudackov, and S. Hammes-Schiffer, "Proton-coupled electron transfer in soybean lipoxygenase," J. Am. Chem. Soc. 126, 5763-5775 (2004). S. Hammes-Schiffer, "Hydrogen tunneling and protein motion in enzyme reactions," Acc. Chem. Res. 39, 93-100 (2006). S. Hammes-Schiffer and S. J. Benkovic, "Relating protein motion to catalysis," Annual Reviews of Biochemistry 75, 519-541 (2006).