QM/MM Protocol for Direct Molecular Dynamics of Chemical Reactions in Solution: The Water-Accelerated Diels–Alder Reaction

We describe a solvent-perturbed transition state (SPTS) sampling scheme for simulating chemical reaction dynamics in condensed phase. The method, adapted from Truhlar and Gao’s ensemble-averaged variational transition state theory, includes the effect of instantaneous solvent configuration on the potential energy surface of the reacting system (RS) and allows initial conditions for the RS to be sampled quasiclassically by TS normal mode sampling. We use a QM/MM model with direct dynamics, in which QM forces of the RS are computed at each trajectory point. The SPTS scheme is applied to the acceleration of the Diels–Alder reaction of cyclopentadiene (CP) + methyl vinyl ketone (MVK) in water. We explored the effect of the number of SPTS and of solvent box size on the distribution of bond lengths in the TS. Statistical sampling of the sampling was achieved when distribution of forming bond lengths converged. We describe the region enclosing the partial bond lengths as the transition zone. Transition zones in the gas phase, SMD implicit solvent, QM/MM, and QM/MM+QM (3 water molecules treated by QM) vary according to the ability of the medium to stabilize zwitterionic structures. Mean time gaps between formation of C–C bonds vary from 11 fs for gas phase to 25 fs for QM/MM+QM. Mean H-bond lengths to O­(carbonyl) in QM/MM+QM are 0.14 Å smaller at the TS than in MVK reactant, and the mean O­(carbonyl)–H­(water)–O­(water) angle of H-bonds at the TS is 10° larger than in MVK reactant