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J Comput Aided Mol Des. 2018 Oct;32(10):1059-1073. doi: 10.1007/s10822-018-0144-8. Epub 2018 Aug 6.

Prediction of CB[8] host-guest binding free energies in SAMPL6 using the double-decoupling method.

Author information

1
Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA. kyungreem.han@nih.gov.
2
Laboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Abstract

This study reports the results of binding free energy calculations for CB[8] host-guest systems in the SAMPL6 blind challenge (receipt ID 3z83m). Force-field parameters were developed specific for each of host and guest molecules to improve configurational sampling. We used quantum mechanical (QM) implicit solvent calculations and QM force matching to determine non-bonded (partial atomic charges) and bonded terms, respectively. Free energy calculations were carried out using the double-decoupling method (DDM) combined with Hamiltonian replica exchange method (HREM) and Bennett acceptance ratio (BAR) method. The root mean square error (RMSE) of the predicted values using DDM with respect to the experimental results was 4.32 kcal/mol. The coefficient of determination (R2) and Kendall rank coefficient (τ) were 0.49 and 0.52, respectively, highest of all submissions. In addition, these were compared to the results obtained by umbrella sampling (US) and weighted histogram analysis method (WHAM). Overall, DDM achieved a higher prediction accuracy than the US method. Results are discussed in terms of parameterization and free energy simulations.

KEYWORDS:

Bennett acceptance ratio; Binding free energy; Double-decoupling; Hamiltonian replica exchange; Umbrella sampling; Weighted histogram analysis

PMID:
30084077
DOI:
10.1007/s10822-018-0144-8

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