Combined Molecular Dynamics and Coordinate Driving Method for Automatic Reaction Pathway Search of Reactions in Solution.

Abstract

The combined molecular dynamics and coordinate driving (MD/CD) method is further refined in this work to automatically search reaction pathways for chemical reactions in solution. In this refined MD/CD method, the selective integrated tempering sampling based MD (SITS-MD) simulations are performed to efficiently sample conformers of the reactants in a realistic solution environment. Then, dozens of the reactant/solvent clusters from SITS-MD simulations were used in the subsequent CD step with the quantum mechanics/molecular mechanics (QM/MM) method to generate the reaction pathways. The present MD/CD method is able to search reaction pathways, in which solvent molecules may directly participate. This approach is applied to investigate two reactions without any prior knowledge of the reaction mechanism: Cope elimination of amine oxide in aqueous and dimethyl sulfoxide solutions, and dehydration of methanediol in aqueous solution. For both reactions, our calculations can locate a large number of low-energy reaction pathways. For the dehydration reaction in aqueous solution, free energy barriers for several reaction modes located by the MD/CD method have been obtained from the potential of mean force calculations. Our results show that the most likely reaction mode is the dehydration of methanediol catalyzed by two water molecules. These two illustrative applications demonstrate that the refined MD/CD method is a promising tool in predicting low-energy reaction pathways for reactions in solution.