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Absolute binding free energy calculations of CBClip host–guest systems in the SAMPL5 blind challenge

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Abstract

Herein, we report the absolute binding free energy calculations of CBClip complexes in the SAMPL5 blind challenge. Initial conformations of CBClip complexes were obtained using docking and molecular dynamics simulations. Free energy calculations were performed using thermodynamic integration (TI) with soft-core potentials and Bennett’s acceptance ratio (BAR) method based on a serial insertion scheme. We compared the results obtained with TI simulations with soft-core potentials and Hamiltonian replica exchange simulations with the serial insertion method combined with the BAR method. The results show that the difference between the two methods can be mainly attributed to the van der Waals free energies, suggesting that either the simulations used for TI or the simulations used for BAR, or both are not fully converged and the two sets of simulations may have sampled difference phase space regions. The penalty scores of force field parameters of the 10 guest molecules provided by CHARMM Generalized Force Field can be an indicator of the accuracy of binding free energy calculations. Among our submissions, the combination of docking and TI performed best, which yielded the root mean square deviation of 2.94 kcal/mol and an average unsigned error of 3.41 kcal/mol for the ten guest molecules. These values were best overall among all participants. However, our submissions had little correlation with experiments.

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Acknowledgments

The authors would like to thank R. Pastor for stimulating discussions. The research was supported by the Intramural Research Program of the NIH, NHLBI. Computational resources and services used in this work were provided by the LoBoS cluster of the National Institutes of Health.

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Authors and Affiliations

  1. Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20852, USA

    Juyong Lee, Florentina Tofoleanu, Frank C. Pickard IV, Gerhard König, Jing Huang, Ana Damjanović & Bernard R. Brooks

  2. Department of Pharmaceutical Science, School of Pharmacy, University of Maryland, Baltimore, MD, 20852, USA

    Jing Huang

  3. Department of Chemistry, Seoul National University, Seoul, Republic of Korea

    Minkyung Baek & Chaok Seok

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  1. Juyong Lee
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  2. Florentina Tofoleanu
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Correspondence to Juyong Lee.

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Lee, J., Tofoleanu, F., Pickard, F.C. et al. Absolute binding free energy calculations of CBClip host–guest systems in the SAMPL5 blind challenge. J Comput Aided Mol Des 31, 71–85 (2017). https://doi.org/10.1007/s10822-016-9968-2

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