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Absolute binding free energies for the SAMPL6 cucurbit[8]uril host–guest challenge via the AMOEBA polarizable force field

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Abstract

As part of the SAMPL6 host–guest blind challenge, the AMOEBA force field was applied to calculate the absolute binding free energy for a cucurbit[8]uril host complexed with 14 diverse guests, ranging from small, rigid structures to drug molecules. The AMOEBA results from the initial submission prompted an investigation into aspects of the methodology and parameterization employed. Lessons learned from the blind challenge include: a double annihilation scheme (electrostatics and van der Waals) is needed to obtain proper sampling of guest conformations, annihilation of key torsion parameters of the guest are recommended for flexible guests, and a more thorough analysis of torsion parameters is warranted. When put in to practice with the AMOEBA model, the lessons learned improved the MUE from 2.63 to 1.20 kcal/mol and the RMSE from 3.62 to 1.68 kcal/mol, respectively. Overall, the AMOEBA protocol for determining absolute binding free energies benefitted from participation in the SAMPL6 host–guest blind challenge and the results suggest the implementation of the methodology in future host–guest calculations.

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Acknowledgements

The authors would like to thank the organizers of the D3R/SAMPL6 challenge. JWP wishes to thank the National Institutes of Health NIGMS for financial support via awards R01 GM106137 and R01 GM114237.

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  1. Department of Chemistry, Washington University in St. Louis, Saint Louis, MO, 63130, USA

    Marie L. Laury, Zhi Wang, Aaron S. Gordon & Jay W. Ponder

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  1. Marie L. Laury
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  2. Zhi Wang
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Correspondence to Jay W. Ponder.

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Laury, M.L., Wang, Z., Gordon, A.S. et al. Absolute binding free energies for the SAMPL6 cucurbit[8]uril host–guest challenge via the AMOEBA polarizable force field. J Comput Aided Mol Des 32, 1087–1095 (2018). https://doi.org/10.1007/s10822-018-0147-5

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