Semiclassical WKB dynamics combined with density functional theory (DFT) ab initio calculations and molecular mechanics were used to describe the initial proton transfer from WAT1 to the distal oxygen (O2) in the active site of Cytocrome P450eryf. DFT active site studies demonstrates the crucial role of a water channel assisting the proton transfer and leading to an overall exothermic reaction.

William Miller, Victor Guallar, and Eduardo Coronado, University of California, Berkeley

Research Objectives
This research continues the development of accurate semiclassical methods and extends its application to large biological systems. Specific projects include (1) methodological studies to explore the capabilities of new approximate versions of semiclassical initial value representation (SC-IVR), (2) SC-IVR to study the reaction dynamics in medium-sized systems, (3) semiclassical Wentzel-Kramers-Brillouin (SC-WKB) applications in real-sized enzymatic systems, and (4) ab initio potential surface development.

Computational Approach
Semiclassical molecular dynamics are evaluated under two different approaches, SC-IVR and SC-WKB. SC-IVR evaluates a high dimensional integral over initial conditions for semiclassical trajectories, according to a classical equations of motion. SC-WKB evaluates the mean position of the system following a classical trajectory propagation, where tunneling effects are added in terms of sudden transfer at the different classical turning points along the desired reaction coordinate. The potential energy surface used in SC-WKB is calculated on the flight with QM/MM methods, combining quantum chemistry in the active site with classical mechanics for the rest of the system, which accurately generate energies and gradients on an enzyme potential surface.

Accomplishments
Accomplishments in FY 2000 include: (1) The most rigorous simulations to date of the excited-state time-dependent proton-transfer dynamics associated with the tautomerization reaction of a relatively large polyatomic system. This computational effort requires a separate calculation of a 140-dimensional integral and demands running approximately 10⁷ semiclassical trajectories. (2) The first direct evidence of the protonation in the activation cycle of a member of the P450 family. We have shown that the mechanism only requires an optimal orientation of the bound molecular oxygen and the presence of a dynamically stable hy-drogen bond network. (3) We have extended the Meyer-Miller Hamiltonian to describe nonadiabatic processes of systems with more than two electronic degrees of freedom. (4) We have developed a new SC-IVR methodology to describe tunneling with real trajectories by a mapping approach. (5) A log-derivative formulation of the prefactor term appearing in the SC-IVR propagator has been developed to avoid the branch cut problem which has hampered previous formulations.

Significance
Molecular dynamics simulations that include quantum effects in the description of reaction dynamics offer a powerful approach to elucidate enzymatic reaction mechanisms at the atomic level. Understanding biological chemical processes at the atomic level will have a major impact on the drug and biotechnology industries.

Publications
E. Coronado, V. Batista, and W. H. Miller, “Nonadiabatic photodissociation dynamics of ICN in the à continuum: A semiclassical initial value representation study,” J. Chem. Phys. 112, 5566 (2000).

V. Guallar, V. Batista, and W. H. Miller, "Semiclassical molecular dynamics simulation of intramolecular proton transfer in photo-excited 2-2('-Hydroxyphenil)-oxazole," J. Chem. Phys. (submitted, 2000).

V. Guallar, V. S. Batista, and W. H. Miller, “Semiclassical molecular dynamics simulations of excited state double proton transfer in 7-azaindole dimers,” J. Chem. Phys. 110, 9922 (1999).