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


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.

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Image and statistics provided courtesy of Andrea Rizzi [86]

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    Herein, MM[FM] [which denotes MM with bonded parameters obtained from force matching, charges from RESP(SMD), and LJ from CGenFF] will be referred to simply as FM, and QM will be a placeholder for either B3LYP/LANL2DZ (for guest G13) or B3LYP/6-31G(d) for all other guest/host.


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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. ( and 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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Hudson, P.S., Han, K., Woodcock, H.L. et al. Force matching as a stepping stone to QM/MM CB[8] host/guest binding free energies: a SAMPL6 cautionary tale. J Comput Aided Mol Des 32, 983–999 (2018).

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  • Host–guest
  • Force matching
  • Indirect free energy
  • SAMPL6