Chapter 4 - QM/MM Alchemical Free Energy Simulations: Challenges and Recent Developments

Abstract The difference between free energy changes occurring at two chemical states can be rigorously estimated via alchemical free energy (AFE) simulations. Traditionally, most AFE simulations are carried out under the classical energy potential treatment; then, accuracy and applicability of AFE simulations are limited. Following the natural evolution, employing the quantum mechanical (QM)-based potentials, particularly the combined QM and molecular mechanical (QM/MM) potentials, in AFE simulations is a natural next step. To make such QM/MM AFE simulations routinely applicable and reliable to complex systems, several major challenges have to be met: (1) to ensure structural integrities for robust electronic structural calculations when unphysical states are simulated; (2) to accurately describe long-range electrostatic interactions; and (3) to efficiently sample the configuration space to guarantee free energy convergence when costly QM/MM potentials are applied. This review summarizes recent developments related to these challenges.