Absolute binding free energies for octa-acids and guests in SAMPL5

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• 作者：Florentina Tofoleanu ; Juyong Lee…
• 关键词：Binding free energy simulations ; Thermodynamic integration ; Hamiltonian replica exchange ; Bennett acceptance ratio ; Double decoupling method ; Molecular dynamics simulations ; GalaxyDock ; HG
• 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：107-118
• 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

As part of the SAMPL5 blind prediction challenge, we calculate the absolute binding free energies of six guest molecules to an octa-acid (OAH) and to a methylated octa-acid (OAMe). We use the double decoupling method via thermodynamic integration (TI) or Hamiltonian replica exchange in connection with the Bennett acceptance ratio (HREM-BAR). We produce the binding poses either through manual docking or by using GalaxyDock-HG, a docking software developed specifically for this study. The root mean square deviations for our most accurate predictions are 1.4 kcal mol−1 for OAH with TI and 1.9 kcal mol−1 for OAMe with HREM-BAR. Our best results for OAMe were obtained for systems with ionic concentrations corresponding to the ionic strength of the experimental solution. The most problematic system contains a halogenated guest. Our attempt to model the σ-hole of the bromine using a constrained off-site point charge, does not improve results. We use results from molecular dynamics simulations to argue that the distinct binding affinities of this guest to OAH and OAMe are due to a difference in the flexibility of the host. We believe that the results of this extensive analysis of host-guest complexes will help improve the protocol used in predicting binding affinities for larger systems, such as protein-substrate compounds.