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


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.

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This article was made possible in part by NIH grants R01GM061300 and U01GM111528, and by Air Force Office of Scientific Research (AFOSR) Basic Research Initiative (BRI) grant (FA9550-12-1-644 0414). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or AFOSR. MKG has an equity interest in and is a cofounder and scientific advisor of VeraChem LLC. We thank Prof. Bruce Gibb for providing the octa-acid experimental data for SAMPL5.

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Correspondence to Michael K. Gilson.

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Yin, J., Henriksen, N.M., Slochower, D.R. et al. The SAMPL5 host–guest challenge: computing binding free energies and enthalpies from explicit solvent simulations by the attach-pull-release (APR) method. J Comput Aided Mol Des 31, 133–145 (2017).

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  • SAMPL5
  • Binding free energy
  • Binding enthalpy
  • Host–guest
  • Force field
  • Water model