Efficient Approach to Reactive Molecular Dynamics with Accurate Forces.

Abstract

Density functional theory is a powerful and efficient method for calculating potential energy surfaces for chemical reactions, but its application to complex systems, such as reactions in enzymes, is often prohibitively expensive, even when high-level theory is applied only to a primary subsystem, such as an active site, and when the remaining system is treated by molecular mechanics. Here we show how the combination of multiconfiguration molecular mechanics with charge response kernels can speed up such calculations by three or more orders of magnitude. The resulting method, called electrostatically embedded multiconfiguration molecular mechanics, is illustrated by calculating the free energy of activation profile for the dehalogenation of 1,2-dichloroethane by haloalkane dehalogenase. This shows how hybrid density functionals or other high-level electronic structure methods can now be used efficiently in simulations that require extensive sampling, such as for calculating free energy profiles along a high-barrier reaction coordinate.