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Journal of Computer-Aided Molecular Design

, Volume 32, Issue 10, pp 1087–1095 | Cite as

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

  • Marie L. Laury
  • Zhi Wang
  • Aaron S. Gordon
  • Jay W. Ponder
Article

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.

Keywords

Absolute binding free energy Cucurbit[8]uril Force field AMOEBA 

Notes

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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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of ChemistryWashington University in St. LouisSaint LouisUSA

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