Accelerating Ab Initio Quantum Mechanical and Molecular Mechanical (QM/MM) Molecular Dynamics Simulations with Multiple Time Step Integration and a Recalibrated Semiempirical QM/MM Hamiltonian.

Molecular dynamics (MD) simulations employing ab initio quantum mechanical and molecular mechanical (ai-QM/MM) potentials are considered to be the state of the art, but the high computational cost associated with the ai-QM calculations remains a theoretical challenge for their routine application. Here, we present a modified protocol of the multiple time step (MTS) method for accelerating ai-QM/MM MD simulations of condensed-phase reactions. Within a previous MTS protocol [Nam J. Chem. Theory Comput. 2014, 10, 4175], reference forces are evaluated using a low-level (semiempirical QM/MM) Hamiltonian and employed at inner time steps to propagate the nuclear motions. Correction forces, which arise from the force differences between high-level (ai-QM/MM) and low-level Hamiltonians, are applied at outer time steps, where the MTS algorithm allows the time-reversible integration of the correction forces. To increase the outer step size, which is bound by the highest-frequency component in the correction forces, the semiempirical QM Hamiltonian is recalibrated in this work to minimize the magnitude of the correction forces. The remaining high-frequency modes, which are mainly bond stretches involving hydrogen atoms, are then removed from the correction forces. When combined with a Langevin or SIN(R) thermostat, the modified MTS-QM/MM scheme remains robust with an up to 8 (with Langevin) or 10 fs (with SIN(R)) outer time step (with 1 fs inner time steps) for the chorismate mutase system. This leads to an over 5-fold speedup over standard ai-QM/MM simulations, without sacrificing the accuracy in the predicted free energy profile of the reaction.