Hybrid approach for the dynamical simulation of proton and hydride transfer in solution and proteins

A hybrid approach for simulating proton and hydride transfer reactions in solution and proteins is described. The electronic quantum effects are incorporated with an empirical valence bond potential. The nuclear quantum effects are included with a mixed quantum-classical molecular dynamics method in which the transferring hydrogen nuclei are represented by multidimensional vibrational wavefunctions. The free energy profiles are obtained as functions of a collective reaction coordinate, and a mapping or umbrella potential is utilized to drive the reaction over the barrier for infrequent events. The vibrationally adiabatic nuclear quantum effects are incorporated into the free energy profiles. The dynamics are described with the molecular dynamics with quantum transitions (MDQT) surface hopping method, which incorporates vibrationally non-adiabatic effects. The MDQT method is combined with a reactive flux approach to calculate the transmission coefficient and to investigate the real-time dynamics of reactive trajectories. Nuclear quantum effects such as zero point energy, hydrogen tunnelling and non-adiabatic transitions, as well as the dynamics of the solvent and protein environment, are included during the generation of the free energy profiles and dynamical trajectories. This methodology provides detailed mechanistic information at the molecular level and allows the calculation of rates and kinetic isotope effects. The feasibility of this approach is illustrated through an application to hydride transfer in the enzyme liver alcohol dehydrogenase. This approach may be extended for use with mixed quantum mechanical-molecular mechanical potentials and alternative mixed quantum-classical molecular dynamics methods. It has also been generalized for multiple proton and protoncoupled electron transfer reactions.