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 s olution and proteins is described. The electronic quantum effects are incor porated with an empirical valence bond potential. The nuclear quantum effec ts 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 functi ons of a collective reaction coordinate, and a mapping or umbrella potentia l 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 dyn amics with quantum transitions (MDQT) surface hopping method, which incorpo rates 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 quantu m 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 dynami cal trajectories. This methodology provides detailed mechanistic informatio n at the molecular level and allows the calculation of rates and kinetic is otope effects. The feasibility of this approach is illustrated through an a pplication to hydride transfer in the enzyme liver alcohol dehydrogenase. T his approach may be extended for use with mixed quantum mechanical-molecula r mechanical potentials and alternative mixed quantum-classical molecular d ynamics methods. It has also been generalized for multiple proton and proto n-coupled electron transfer reactions.