Accelerating QM/MM Free Energy Computations via Intramolecular Force Matching

Phillip S. Hudson; Stefan Boresch; David M. Rogers; H. Lee Woodcock

doi:10.1021/acs.jctc.8b00517

Accelerating QM/MM Free Energy Computations via Intramolecular Force Matching

Phillip S. Hudson, Stefan Boresch, David M. Rogers, H. Lee Woodcock

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	6327-6335
Number of pages	9
Journal	Journal of Chemical Theory and Computation
Volume	14
Issue number	12
DOIs	https://doi.org/10.1021/acs.jctc.8b00517
State	Published - Dec 11 2018
Externally published	Yes

Funding

Further, H.L.W. and P.S.H. thank USF Research Computing (Circe) for their patience and assistance and the NSF for support via their Major Research Instrumentation Program (MRI-1531590). P.S.H. acknowledges funding support from the Intramural Research Program of the NIH, NHLBI. This work was partially supported by the intramural research program of the National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health and employed the high-performance computational capabilities of the LoBoS and Biowulf Linux clusters at the National Institutes of Health (http://www.lobos.nih.gov and https://hpc.nih.gov). Finally, S.B. gratefully acknowledges support for this work from the Austrian Science Fund/FWF (P31024). Notes The authors declare no competing financial interest. *E-mail: [email protected]. *E-mail: [email protected]. ORCID H. Lee Woodcock: 0000-0003-3539-273X Funding H.L.W. would like to highlight that this material is based upon work supported by the National Science Foundation under CHE-1464946. Additionally, research reported in this publication was supported by NIGMS of the National Institutes of Health under award number R01GM129519.

Funders	Funder number
Austrian Science Fund/FWF	P31024
National Science Foundation	MRI-1531590, CHE-1464946
National Institutes of Health
National Heart, Lung, and Blood Institute
National Institute of General Medical Sciences	R01GM129519
University of San Francisco

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Accelerating QM/MM Free Energy Computations via Intramolecular Force Matching

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