Collective Reaction Coordinate for Hybrid Quantum and Molecular Mechanics Simulations: A Case Study of the Hydride Transfer in Dihydrofolate Reductase.

The optimal description of the reaction coordinate in chemical systems is of great importance in simulating condensed phase reactions. In the current work, we present a collective reaction coordinate which is composed of several geometric coordinates which represent structural progress during the course of a hydride transfer reaction: the antisymmetric reactive stretch coordinate, the donor-acceptor distance (DAD) coordinate, and an orbital rehybridization coordinate. In this approach, the former coordinate serves as a distinguished reaction coordinate, while the latter two serve as environmental, Marcus-type inner-sphere reorganization coordinates. The classical free energy surface is obtained from multidimensional quantum mechanics-molecular mechanics (QM/MM) potential of mean force (PMF) simulations in conjunction with a general and efficient multidimensional weighted histogram method implementation. The minimum free energy path, or the collective reaction coordinate, connecting the dividing hypersurface to reactants and products, is obtained using an iterative scheme. In this approach, the string method is used to find the minimum free energy path. This path guides the multidimensional sampling, while the path is adaptively refined until convergence is achieved. As a model system, we choose the hydride transfer reaction in Escherichia coli dihydrofolate reductase (ecDHFR) using a recently developed accurate semiempirical potential energy surface. To estimate the advantages of the collective reaction coordinate, we perform activated dynamics simulations to obtain the reaction transmission coefficient. The results show that the combination of a distinguished reaction coordinate and an inner-sphere reorganization coordinate considerably reduces the dividing surface recrossing.