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J Chem Theory Comput. 2018 Dec 11;14(12):6327-6335. doi: 10.1021/acs.jctc.8b00517. Epub 2018 Nov 15.

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

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Department of Chemistry , University of South Florida , 4202 East Fowler Avenue, CHE205 , Tampa , Florida 33620-5250 , United States.
Laboratory of Computational Biology , National Institutes of Health, National Heart, Lung and Blood Institute , 12 South Drive Rm 3053 , Bethesda , Maryland 20892-5690 , United States.
Faculty of Chemistry, Department of Computational Biological Chemistry , University of Vienna , Währingerstraße 17 , A-1090 Vienna , Austria.


The calculation of free energy differences between levels of theory has numerous potential pitfalls. Chief among 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 straightforward 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 reparametrizing 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 test cases and results in vastly improved convergence of free energy simulations.


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