Hydride transfer in liver alcohol dehydrogenase: quantum dynamics, kinetic isotope effects, and role of enzyme motion.

The quantum dynamics of the hydride transfer reaction catalyzed by liver alcohol dehydrogenase (LADH) are studied with real-time dynamical simulations including the motion of the entire solvated enzyme. The electronic quantum effects are incorporated with an empirical valence bond potential, and the nuclear quantum effects of the transferring hydrogen are incorporated with a mixed quantum/classical molecular dynamics method in which the transferring hydrogen nucleus is represented by a three-dimensional vibrational wave function. The equilibrium transition state theory rate constants are determined from the adiabatic quantum free energy profiles, which include the free energy of the zero point motion for the transferring nucleus. The nonequilibrium dynamical effects are determined by calculating the transmission coefficients with a reactive flux scheme based on real-time molecular dynamics with quantum transitions (MDQT) surface hopping trajectories. The values of nearly unity for these transmission coefficients imply that nonequilibrium dynamical effects such as barrier recrossings are not dominant for this reaction. The calculated deuterium and tritium kinetic isotope effects for the overall rate agree with experimental results. These simulations elucidate the fundamental nature of the nuclear quantum effects and provide evidence of hydrogen tunneling in the direction along the donor-acceptor axis. An analysis of the geometrical parameters during the equilibrium and nonequilibrium simulations provides insight into the relation between specific enzyme motions and enzyme activity. The donor-acceptor distance, the catalytic zinc-substrate oxygen distance, and the coenzyme (NAD(+)/NADH) ring angles are found to strongly impact the activation free energy barrier, while the donor-acceptor distance and one of the coenzyme ring angles are found to be correlated to the degree of barrier recrossing. The distance between VAL-203 and the reactive center is found to significantly impact the activation free energy but not the degree of barrier recrossing. This result indicates that the experimentally observed effect of mutating VAL-203 on the enzyme activity is due to the alteration of the equilibrium free energy difference between the transition state and the reactant rather than nonequilibrium dynamical factors. The promoting motion of VAL-203 is characterized in terms of steric interactions involving THR-178 and the coenzyme.

Theoretical study of electron, proton, and proton-coupled electron transfer in iron bi-imidazoline complexes.

A comparative theoretical investigation of single electron transfer (ET), single proton transfer (PT), and proton-coupled electron transfer (PCET) reactions in iron bi-imidazoline complexes is presented. These calculations are motivated by experimental studies showing that the rates of ET and PCET are similar and are both slower than the rate of PT for these systems (Roth, J. P.; Lovel, S.; Mayer, J. M. J. Am. Chem. Soc. 2000, 122, 5486). The theoretical calculations are based on a multistate continuum theory, in which the solute is described by a multistate valence bond model, the transferring hydrogen nucleus is treated quantum mechanically, and the solvent is represented as a dielectric continuum. For electronically nonadiabatic electron transfer, the rate expressions for ET and PCET depend on the inner-sphere (solute) and outer-sphere (solvent) reorganization energies and on the electronic coupling, which is averaged over the reactant and product proton vibrational wave functions for PCET. The small overlap of the proton vibrational wave functions localized on opposite sides of the proton transfer interface decreases the coupling for PCET relative to ET. The theory accurately reproduces the experimentally measured rates and deuterium kinetic isotope effects for ET and PCET. The calculations indicate that the similarity of the rates for ET and PCET is due mainly to the compensation of the smaller outer-sphere solvent reorganization energy for PCET by the larger coupling for ET. The moderate kinetic isotope effect for PCET arises from the relatively short proton transfer distance. The PT reaction is found to be dominated by solute reorganization (with very small solvent reorganization energy) and to be electronically adiabatic, leading to a fundamentally different mechanism that accounts for the faster rate.

Theoretical perspectives on proton-coupled electron transfer reactions.

This Account presents a theoretical formulation for proton-coupled electron transfer reactions. The active electrons and transferring protons are treated quantum mechanically, and the free energy surfaces are obtained as functions of collective solvent coordinates corresponding to the proton and electron transfer reactions. Rate expressions have been derived in the relevant limits, and methodology for including the dynamical effects of the solvent and protein has been developed. This theoretical framework allows predictions of rates, mechanisms, and kinetic isotope effects for proton-coupled electron transfer reactions.