Resolving the problem of trapped water in binding cavities: prediction of host–guest binding free energies in the SAMPL5 challenge by funnel metadynamics

Bhakat, Soumendranath; Söderhjelm, Pär

doi:10.1007/s10822-016-9948-6

Cited by 20 publications

(41 citation statements)

References 40 publications

(50 reference statements)

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“…It is not immediately clear why the Metadynamics and APR-TIP3P differ, as the force fields used appear to match, but it is worth noting that the Metadynamics calculations actually provided relative binding free energies, which were converted into absolute binding free energies for submission by referring to a known octa-acid guest result from SAMPL4. The accurate absolute binding free energies cannot be obtained by Metadynamics due to the special treatment of the unbound state as a “dry state”, in which all water molecules were restrained from entering the host cavity [56]. …”

Section: Resultsmentioning

confidence: 99%

Overview of the SAMPL5 host–guest challenge: Are we doing better?

Yin

Henriksen

Slochower

et al. 2016

J Comput Aided Mol Des

182

243

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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.

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Section: Resultsmentioning

confidence: 99%

Overview of the SAMPL5 host–guest challenge: Are we doing better?

Yin

Henriksen

Slochower

et al. 2016

J Comput Aided Mol Des

182

243

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“…This poses significant challenges for some approaches, such as metadynamics, where deliberately restraining water to stay out of the cavity when the host is not bound (and computing the free energy of doing so) can help convergence (8), and perhaps for other methods as well.…”

Section: Benchmark Systems For Binding Predictionmentioning

confidence: 99%

“…Thus, there are uncertainties as to the host protonation state (91, 32), which perhaps also could be modulated by guest binding. Several groups used different methods but the same force field and water model in SAMPL5, with rather varied levels of success because of discrepancies in calculated free energies (136, 10, 8). However, some of these issues were resolved in follow-up work (8), bringing the methods into fairly good agreement for the majority of cases (137, 10).…”

Section: Benchmark Systems For Binding Predictionmentioning

confidence: 99%

“…Physical pathway methods provide the standard binding free energy by computing the reversible work of, in effect, pulling the ligand out of the binding site. Although, by definition, the pathway used must be a physical one that could occur in nature, it need not be probable, and improbable pathways, governed by an order parameter specifying how far the ligand is from the binding site, are often used (133, 138, 122, 50, 54, 8). In addition, artificial restraints may be useful to avoid sampling problems in the face of often complex barriers along the pathway (133, 122, 50, 54, 8).…”

Section: Introductionmentioning

confidence: 99%

“…Although, by definition, the pathway used must be a physical one that could occur in nature, it need not be probable, and improbable pathways, governed by an order parameter specifying how far the ligand is from the binding site, are often used (133, 138, 122, 50, 54, 8). In addition, artificial restraints may be useful to avoid sampling problems in the face of often complex barriers along the pathway (133, 122, 50, 54, 8). By contrast, alchemical pathway methods artificially decouple the ligand from the binding site and then recouple it to solution from the protein (58, 51, 45, 9, 80).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Predicting Binding Free Energies: Frontiers and Benchmarks

Mobley

Gilson

2017

Annu. Rev. Biophys.

312

325

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Binding free energy calculations based on molecular simulations provide predicted affinities for biomolecular complexes. These calculations begin with a detailed description of a system, including its chemical composition and the interactions between its components. Simulations of the system are then used to compute thermodynamic information, such as binding affinities. Because of their promise for guiding molecular design, these calculations have recently begun to see widespread applications in early stage drug discovery. However, many challenges remain to make them a robust and reliable tool. Here, we highlight key challenges facing these calculations, describe known examples of these challenges, and call for the designation of standard community benchmark test systems that will help the research community generate and evaluate progress. In our view, progress will require careful assessment and evaluation of new methods, force fields, and modeling innovations on well-characterized benchmark systems, and we lay out our vision for how this can be achieved.

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Detailed potential of mean force studies on host–guest systems from the SAMPL6 challenge

Song

Bansal

Zhang

et al. 2018

J Comput Aided Mol Des

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Accurately predicting receptor-ligand binding free energies is one of the holy grails of computational chemistry with many applications in chemistry and biology. Many successes have been reported, but issues relating to sampling and force field accuracy remain significant issues affecting our ability to reliably calculate binding free energies. In order to explore these issues in more detail we have examined a series of small host-guest complexes from the SAMPL6 blind challenge, namely octa-acids (OAs)-guest complexes and Curcurbit[8]uril (CB8)-guest complexes. Specifically, potential of mean force studies using umbrella sampling combined with the weighted histogram method were carried out on both systems with both known and unknown binding affinities. We find that using standard force fields and straightforward simulation protocols we are able to obtain satisfactory results, but that simply scaling our results allows us to significantly improve our predictive ability for the unknown test sets: the overall RMSD of the binding free energy versus experiment is reduced from 5.59 to 2.36 kcal/mol; for the CB8 test system, the RMSD goes from 8.04 to 3.51 kcal/mol, while for the OAs test system, the RSMD goes from 2.89 to 0.95 kcal/mol. The scaling approach was inspired by studies on structurally related known benchmark sets: by simply scaling, the RMSD was reduced from 6.23 to 1.19 kcal/mol and from 2.96 to 0.62 kcal/mol for the CB8 benchmark system and the OA benchmark system, respectively. We find this scaling procedure to correct absolute binding affinities to be highly effective especially when working across a "congeneric" series with similar charge states. It is less successful when applied to mixed ligands with varied charges and chemical characteristics, but improvement is still realized in the present case. This approach suggests that there are large systematic errors in absolute binding free energy calculations that can be straightforwardly accounted for using a scaling procedure. Random errors are still an issue, but near chemical accuracy can be obtained using the present strategy in select cases.

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Resolving the problem of trapped water in binding cavities: prediction of host–guest binding free energies in the SAMPL5 challenge by funnel metadynamics

Cited by 20 publications

References 40 publications

Overview of the SAMPL5 host–guest challenge: Are we doing better?

Overview of the SAMPL5 host–guest challenge: Are we doing better?

Predicting Binding Free Energies: Frontiers and Benchmarks

Detailed potential of mean force studies on host–guest systems from the SAMPL6 challenge

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