Quantitative analysis and correction of quantum mechanics/molecular mechanics boundary artifacts in adaptive QM/MM methods

The incorporation of quantum chemical effects of solvation into molecular dynamics simulation has been a challenging issue due to solvent diffusion. To this end, various adaptive quantum mechanics/molecular mechanics (QM/MM) methods have been proposed, in which free solvent exchanges are allowed via a flexible switching of their identities between QM and MM models according to their distances from the QM solute. However, temporal and spatial discontinuities that remain in the standard implementations continue to hamper stable and accurate dynamics simulations using adaptive QM/MM approaches. We previously demonstrated that the size-consistent multi-partitioning (SCMP) method achieved temporal continuity while avoiding spatial discontinuities to some extent. In the present study, however, we demonstrate that the residual spatial discontinuity may lead to severe problems under certain conditions; via quantitative analysis, we show that not only adaptive QM/MM but also all multiscale approaches might share these problems implicitly, which have not been investigated in depth so far. To alleviate these artifacts, we propose a correction based on the SCMP approach and conduct benchmark simulations using bulk water systems.