Absolute binding free energy calculations of CBClip host–guest systems in the SAMPL5 blind challenge
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- 作者：Juyong Lee ; Florentina Tofoleanu…
- 关键词：Absolute binding free energy calculation ; Hamiltonian replica exchange ; Thermodynamic integration ; Bennett’s acceptance ratio ; Double decoupling scheme ; Host ; guest complexes ; Constant ; pH simulation
- 刊名：Journal of Computer-Aided Molecular Design
- 出版年：2017
- 出版时间：January 2017
- 年：2017
- 卷：31
- 期：1
- 页码：71-85
- 全文大小：
- 刊物类别：Chemistry and Materials Science
- 刊物主题：Physical Chemistry; Computer Applications in Chemistry; Animal Anatomy / Morphology / Histology;
- 出版者：Springer International Publishing
- ISSN：1573-4951
- 卷排序：31
文摘
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.