Obtaining accurate free energies via the indirect approach to free energy simulation (FES) is prohibited by the need to compute free energy differences between high (e.g., quantum) and low (e.g., classical) levels of theory. This step proves to be particularly problematic, as many have found, due to the poor configurational overlap in intramolecular degrees of freedom (e.g., bonds, angles, dihedrals, etc.)  between levels of theory. Herein, we demonstrate the by reparameterizing classical intramolecular potentials to reproduce high-level forces; it is possible to create a new ``force matched'' low-level ensemble that has appreciably more configurational overlap with the target high level of theory and thus facilitating indirect FES.

Enhancing QM/MM indirect free energy simulations with intramolecular force matching

254th National Meeting (2017)

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