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Thermodynamic integration to predict host-guest binding affinities

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Abstract

An alchemical free energy method with explicit solvent molecular dynamics simulations was applied as part of the blind prediction contest SAMPL3 to calculate binding free energies for seven guests to an acyclic cucurbit-[n]uril host. The predictions included determination of protonation states for both host and guests, docking pose generation, and binding free energy calculations using thermodynamic integration. We found a root mean square error (RMSE) of \(3.6\,\hbox{kcal}\,\hbox{mol}^{-1}\) from the reference experimental results, with an R 2 correlation of 0.51. The agreement with experiment for the largest contributor to this error, guest 6, is improved by \(1.7\,\hbox{kcal}\,\hbox{mol}^{-1}\) when a periodicity-induced free energy correction is applied. The corrections for the other ligands were significantly smaller, and altogether the RMSE was reduced by \(0.4 \,\hbox{kcal}\,\hbox{mol}^{-1}\). We link properties of the host-guest systems during simulation to errors in the computed free energies. Overall, we show that charged host-guest systems studied here, initialized in unconfirmed docking poses, present a challenge to accurate alchemical simulation methods.

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Acknowledgments

The authors thank the members of the McCammon group for useful discussions, and Gabriel Rocklin from the Shoichet/Dill group for help in determining the periodicity-induced free energy correction. This work was supported, in part, by the National Institutes of Health, the National Science Foundation, the National Biomedical Computational Resource, and the Howard Hughes Medical Institute. We thank the Center for Theoretical Biological Physics (NSF Grant PHY-0822283), and the Texas Advanced Computer Center (grant TG-MCA93S013) for distributed computing resources. J. M. Ortiz-Sánchez acknowledges the Fulbright Commission/Generalitat de Catalunya Program and the Generalitat de Catalunya for a Fulbright and a Beatriu de Pinos postdoctoral grants, respectively. J. Wereszczynski acknowledges support by Award Number F32GM093581 from the National Institute of General Medical Sciences. The project content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of General Medical Sciences or the National Institutes of Health.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, CA, USA

    Morgan Lawrenz, Jeff Wereszczynski, Juan Manuel Ortiz-Sánchez, Sara E. Nichols & J. Andrew McCammon

  2. Department of Pharmacology, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA

    Sara E. Nichols & J. Andrew McCammon

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  1. Morgan Lawrenz
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  2. Jeff Wereszczynski
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  3. Juan Manuel Ortiz-Sánchez
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  4. Sara E. Nichols
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  5. J. Andrew McCammon
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Correspondence to Morgan Lawrenz.

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Lawrenz, M., Wereszczynski, J., Ortiz-Sánchez, J.M. et al. Thermodynamic integration to predict host-guest binding affinities. J Comput Aided Mol Des 26, 569–576 (2012). https://doi.org/10.1007/s10822-012-9542-5

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