High-performance QM/MM Enhanced Sampling Molecular Dynamics Simulations with GENESIS SPDYN and QSimulate-QM.

A new module for quantum mechanical/molecular mechanical (QM/MM) calculations is implemented in a molecular dynamics (MD) program, SPDYN in GENESIS, interfaced with an electronic structure program, QSimulate-QM. The periodic boundary condition (PBC) in QM/MM simulation is incorporated via QM calculation in real space with duplicated MM charges and particle mesh Ewald (PME) calculation with QM and MM charges. A highly optimized code is implemented in QSimulate-QM, particularly for the density functional tight-binding (DFTB) method, where the interaction between the QM and MM regions is computed utilizing multipole expansions. Together with highly parallelized algorithms in SPDYN, the developed program performs MD simulations based on DFTB in the QM size of ∼100 atoms and MM of ∼100,000 atoms with a better performance than 1 ns/day using one computer node. This feature paves the way for QM/MM-MD enhanced sampling simulations. Various enhanced sampling methods in GENESIS, namely, generalized replica exchange solute tempering (gREST), replica-exchange umbrella sampling (REUS), and path sampling with the string method, are demonstrated at the QM/MM level to compute the Ramachandran plot of alanine dipeptide and the potential of mean force (PMF) of a proton transfer reaction in an enzyme.