Prof. Jiali Gao
Department of Chemistry
University of Minnesota
Minneapolis, MN

Monday, May 13, 2013
3:00 pm (CT)
3269 Beckman Institute

Abstract

An important question in enzymology is the precise mechanism by which large-scale motions and fast, local fluctuations are connected to the chemical transformation to lower the free energy barrier. In this talk, I will describe a combined QM/MM study of dihydrofolate reductase (DHFR), revealing that distant mutations (M42W and G121V) significantly reduce the dynamic motions of a flexible loop, called M20 loop, at the transition state of the catalyzed hydride transfer. The diminished rate enhancement in the mutant enzyme is a result of protein dynamics knock-out, an idea that was recently explored experimentally on other mutations in DHFR. The computational results helped to interpret the experimental observations of increased entropic barrier, reduced catalytic activity, and altered kinetic behaviors, including temperature- dependence of kinetic isotope effects (KIE). Then, I will turn my attention to theory and discuss the development of a fully quantum mechanical force field (QMFF) for dynamical simulations of proteins. Unlike traditional approaches that use quantum mechanical results and experimental data to parameterize empirical potentials, the QMFF uses a quantum mechanical framework to represent intramolecular and intermolecular interactions. Thus, the internal energy terms used in molecular mechanics are replaced by a quantum mechanical formalism that naturally includes electronic polarization due to intermolecular interactions and its effects on the force constants of the intramolecular force field. I will present results from dynamics simulations using NAMD with such a QMFF.