A combined treatment of hydration and dynamical effects for the modeling of host–guest binding thermodynamics: the SAMPL5 blinded challenge

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• 作者：Rajat Kumar Pal ; Kamran Haider ; Divya Kaur…
• 关键词：SAMPL5 ; Hydration Site Analysis (HSA) ; Debye–Hückel ; Salt effects ; AGBNP2 ; BEDAM
• 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：29-44
• 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 blinded experiment, we computed the absolute binding free energies of 22 host–guest complexes employing a novel approach based on the BEDAM single-decoupling alchemical free energy protocol with parallel replica exchange conformational sampling and the AGBNP2 implicit solvation model specifically customized to treat the effect of water displacement as modeled by the Hydration Site Analysis method with explicit solvation. Initial predictions were affected by the lack of treatment of ionic charge screening, which is very significant for these highly charged hosts, and resulted in poor relative ranking of negatively versus positively charged guests. Binding free energies obtained with Debye–Hückel treatment of salt effects were in good agreement with experimental measurements. Water displacement effects contributed favorably and very significantly to the observed binding affinities; without it, the modeling predictions would have grossly underestimated binding. The work validates the implicit/explicit solvation approach employed here and it shows that comprehensive physical models can be effective at predicting binding affinities of molecular complexes requiring accurate treatment of conformational dynamics and hydration.