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Journal of Computer-Aided Molecular Design

, Volume 32, Issue 10, pp 983–999 | Cite as

Force matching as a stepping stone to QM/MM CB[8] host/guest binding free energies: a SAMPL6 cautionary tale

  • Phillip S. Hudson
  • Kyungreem Han
  • H. Lee Woodcock
  • Bernard R. Brooks
Article
  • 149 Downloads

Abstract

Use of quantum mechanical/molecular mechanical (QM/MM) methods in binding free energy calculations, particularly in the SAMPL challenge, often fail to achieve improvement over standard additive (MM) force fields. Frequently, the implementation is through use of reference potentials, or the so-called “indirect approach”, and inherently relies on sufficient overlap existing between MM and QM/MM configurational spaces. This overlap is generally poor, particularly for the use of free energy perturbation to perform the MM to QM/MM free energy correction at the end states of interest (e.g., bound and unbound states). However, by utilizing MM parameters that best reproduce forces obtained at the desired QM level of theory, it is possible to lessen the configurational disparity between MM and QM/MM. To this end, we sought to use force matching to generate MM parameters for the SAMPL6 CB[8] host–guest binding challenge, classically compute binding free energies, and apply energetic end state corrections to obtain QM/MM binding free energy differences. For the standard set of 11 molecules and the bonus set (including three additional challenge molecules), error statistics, such as the root mean square deviation (RMSE) were moderately poor (5.5 and 5.4 kcal/mol). Correlation statistics, however, were in the top two for both standard and bonus set submissions (\(R^{2}\) of 0.42 and 0.26, \(\tau\) of 0.64 and 0.47 respectively). High RMSE and moderate correlation strongly indicated the presence of systematic error. Identifiable issues were ameliorated for two of the guest molecules, resulting in a reduction of error and pointing to strong prospects for the future use of this methodology.

Keywords

Host–guest Force matching Indirect free energy SAMPL6 

Notes

Acknowledgements

The authors would like to thank Rubén Meana-Pañeda, Richard Venable, John Legato, Qiao Zheng, and Michael R. Jones for technical assistance. We extend our gratitude to Erin Cassidy Hendrick, Ian Bookhamer, Stefan Boresch, Florentina Tofoleanu, and Andrea Rizzi for helpful comments on the manuscript and general insights. 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 http://biowulf.nih.gov). PSH acknowledges funding support from the Intramural Research Program of the NIH, NHLBI. HLW would like to highlight that this material is based upon work supported by the National Science Foundation under CHE-1464946.

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Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2018

Authors and Affiliations

  1. 1.Laboratory of Computational BiologyNational Heart, Lung and Blood Institute, National Institutes of HealthBethesdaUSA
  2. 2.Department of ChemistryUniversity of South FloridaTampaUSA

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