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

ABSTRACT: 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 ?-cyclodextrin (?CD) 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.

SUBMITTER: Yin J

PROVIDER: S-EPMC5241238 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Yin Jian J Henriksen Niel M NM Slochower David R DR Gilson Michael K MK

Journal of computer-aided molecular design 20160916 1

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 ...[more]

PMID: 27638809

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Project description:We have tried to calculate the free energy for the binding of six small ligands to two variants of the octa-acid deep cavitand host in the SAMPL5 blind challenge. We employed structures minimised with dispersion-corrected density-functional theory with small basis sets and energies were calculated using large basis sets. Solvation energies were calculated with continuum methods and thermostatistical corrections were obtained from frequencies calculated at the HF-3c level. Care was taken to minimise the effects of the flexibility of the host by keeping the complexes as symmetric and similar as possible. In some calculations, the large net charge of the host was reduced by removing the propionate and benzoate groups. In addition, the effect of a restricted molecular dynamics sampling of structures was tested. Finally, we tried to improve the energies by using the DLPNO-CCSD(T) approach. Unfortunately, results of quite poor quality were obtained, with no correlation to the experimental data, systematically too positive affinities (by ~50 kJ/mol) and a mean absolute error (after removal of the systematic error) of 11-16 kJ/mol. DLPNO-CCSD(T) did not improve the results, so the accuracy is not limited by the energy function. Instead, four likely sources of errors were identified: first, the minimised structures were often incorrect, owing to the omission of explicit solvent. They could be partly improved by performing the minimisations in a continuum solvent with four water molecules around the charged groups of the ligands. Second, some ligands could bind in several different conformations, requiring sampling of reasonable structures. Third, there is an indication the continuum-solvation model has problems to accurately describe the binding of both the negatively and positively charged guest molecules. Fourth, different methods to calculate the thermostatistical corrections gave results that differed by up to 30 kJ/mol and there is an indication that HF-3c overestimates the entropy term. In conclusion, it is a challenge to calculate binding affinities for this octa-acid system with quantum-mechanical methods.

Project description:The ability to computationally predict protein-small molecule binding affinities with high accuracy would accelerate drug discovery and reduce its cost by eliminating rounds of trial-and-error synthesis and experimental evaluation of candidate ligands. As academic and industrial groups work toward this capability, there is an ongoing need for datasets that can be used to rigorously test new computational methods. Although protein-ligand data are clearly important for this purpose, their size and complexity make it difficult to obtain well-converged results and to troubleshoot computational methods. Host-guest systems offer a valuable alternative class of test cases, as they exemplify noncovalent molecular recognition but are far smaller and simpler. As a consequence, host-guest systems have been part of the prior two rounds of SAMPL prediction exercises, and they also figure in the present SAMPL5 round. In addition to being blinded, and thus avoiding biases that may arise in retrospective studies, the SAMPL challenges have the merit of focusing multiple researchers on a common set of molecular systems, so that methods may be compared and ideas exchanged. The present paper provides an overview of the host-guest component of SAMPL5, which centers on three different hosts, two octa-acids and a glycoluril-based molecular clip, and two different sets of guest molecules, in aqueous solution. A range of methods were applied, including electronic structure calculations with implicit solvent models; methods that combine empirical force fields with implicit solvent models; and explicit solvent free energy simulations. The most reliable methods tend to fall in the latter class, consistent with results in prior SAMPL rounds, but the level of accuracy is still below that sought for reliable computer-aided drug design. Advances in force field accuracy, modeling of protonation equilibria, electronic structure methods, and solvent models, hold promise for future improvements.

Project description:Bromodomains, protein domains involved in epigenetic regulation, are able to bind small molecules with high affinity. In the present study, we report free energy calculations for the binding of seven ligands to the first BRD4 bromodomain, using the attach-pull-release (APR) method to compute the reversible work of removing the ligands from the binding site and then allowing the protein to relax conformationally. We test three different water models, TIP3P, TIP4PEw, and SPC/E, as well as the GAFF and GAFF2 parameter sets for the ligands. Our simulations show that the apo crystal structure of BRD4 is only metastable, with a structural transition happening in the absence of the ligand typically after 20 ns of simulation. We compute the free energy change for this transition with a separate APR calculation on the free protein and include its contribution to the ligand binding free energies, which generally causes an underestimation of the affinities. By testing different water models and ligand parameters, we are also able to assess their influence in our results and determine which one produces the best agreement with the experimental data. Both free energies associated with the conformational change and ligand binding are affected by the choice of water model, with the two sets of ligand parameters affecting their binding free energies to a lesser degree. Across all six combinations of water model and ligand potential function, the Pearson correlation coefficients between calculated and experimental binding free energies range from 0.55 to 0.83, and the root-mean-square errors range from 1.4-3.2 kcal/mol. The current protocol also yields encouraging preliminary results when used to assess the relative stability of ligand poses generated by docking or other methods, as illustrated for two different ligands. Our method takes advantage of the high performance provided by graphics processing units and can readily be applied to other ligands as well as other protein systems.

Dataset Information

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

Publications

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

Similar Datasets

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