title: Hybrid Quantum and Classical Simulations of the Dihydrofolate Reductase Catalyzed Hydride Transfer Reaction on an Accurate Semi-Empirical Potential Energy Surface.
abstract: Dihydrofolate reductase (DHFR) catalyzes the reduction of 7,8-dihydrofolate by nicotinamide adenine dinucleotide phosphate hydride (NADPH) to form 5,6,7,8-tetrahydrofolate and oxidized nicotinamide. DHFR is a small, flexible, monomeric protein with no metals or SS bonds and serves as one of the enzymes commonly used to examine basic aspects in enzymology. In the current work, we present extensive benchmark calculations for several model reactions in the gas phase that are relevant to the DHFR catalyzed hydride transfer. To this end, we employ G4MP2 and CBS-QB3 ab initio calculations as well as numerous density functional theory methods. Using these results, we develop two specific reaction parameter (SRP) Hamiltonians based on the semiempirical AM1 method. The first generation SRP Hamiltonian does not account for dispersion, while the second generation SRP accounts for dispersion implicitly via the AM1 core-repulsion functions. These SRP semiempirical Hamiltonians are subsequently used in hybrid quantum mechanics/molecular mechanics simulations of the DHFR catalyzed reaction. Finally, kinetic isotope effects are computed using a mass-perturbation-based path-integral approach.
authors.affiliation: Department of Chemistry, The Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Dvir
authors.initials: D
authors.lastname: Doron
authors.affiliation: Department of Chemistry, The Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors.forename: Dan Thomas
authors.initials: DT
authors.lastname: Major
authors.affiliation: Department of Chemistry, University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: Amnon
authors.initials: A
authors.lastname: Kohen
authors.affiliation: Max-Planck-Institut für Kohlenforschung , Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Thiel
authors.affiliation: Max-Planck-Institut für Kohlenforschung , Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr, Germany.
authors.forename: Xin
authors.initials: X
authors.lastname: Wu