Accelerating QM/MM Free Energy Computations via Intramolecular Force Matching.

The calculation of free energy differences between levels of theory has numerous potential pitfalls. Chief amongst them is the lack of overlap, i.e., ensembles generated at one level of theory (e.g., ``low'') not being good approximations of ensembles at the other (e.g., ``high''). Numerous strategies have been devised to mitigate this issue. However, the most straight-forward approach is to ensure that the ``low'' level ensemble more closely resembles that of the ``high''. Ideally, this is done without increasing computational cost. Herein, we demonstrate that by reparameterizing classical intramolecular potentials to reproduce high level forces (i.e., force matching) configurational overlap between a ``low'' (i.e., classical) and ``high'' (i.e., quantum) level can be significantly improved. This procedure is validated on two challenging test cases and results in vastly improved convergence of free energy simulations.