The SAMPL5 host–guest challenge: computing binding free energies and enthalpies from explicit solvent simulations by the attach-pull-release (APR) method

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• 作者：Jian Yin ; Niel M. Henriksen…
• 关键词：SAMPL5 ; Binding free energy ; Binding enthalpy ; Host–guest ; Force field ; Water model
• 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：133-145
• 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

The absolute binding free energies and binding enthalpies of twelve host–guest systems in the SAMPL5 blind challenge were computed using our attach-pull-release (APR) approach. This method has previously shown good correlations between experimental and calculated binding data in retrospective studies of cucurbit[7]uril (CB7) and β-cyclodextrin (βCD) systems. In the present work, the computed binding free energies for host octa acid (OA or OAH) and tetra-endo-methyl octa-acid (TEMOA or OAMe) with guests are in good agreement with prospective experimental data, with a coefficient of determination (R2) of 0.8 and root-mean-squared error of 1.7 kcal/mol using the TIP3P water model. The binding enthalpy calculations achieve moderate correlations, with R2 of 0.5 and RMSE of 2.5 kcal/mol, for TIP3P water. Calculations using the newly developed OPC water model also show good performance. Furthermore, the present calculations semi-quantitatively capture the experimental trend of enthalpy-entropy compensation observed, and successfully predict guests with the strongest and weakest binding affinity. The most populated binding poses of all twelve systems, based on clustering analysis of 750 ns molecular dynamics (MD) trajectories, were extracted and analyzed. Computational methods using MD simulations and explicit solvent models in a rigorous statistical thermodynamic framework, like APR, can generate reasonable predictions of binding thermodynamics. Especially with continuing improvement in simulation force fields, such methods hold the promise of making substantial contributions to hit identification and lead optimization in the drug discovery process.