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

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Abstract

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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Funding

Funding was provided by National Institutes of Health (Grant No: GM112406).

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  1. Nupur Bansal

    Present address: Biogen Inc., Cambridge, MA, 02142, USA

Authors and Affiliations

  1. Department of Chemistry and the Department of Biochemistry and Molecular Biology, Michigan State University, 578 S. Shaw Lane, East Lansing, MI, 48824, USA

    Lin Frank Song, Nupur Bansal, Zheng Zheng & Kenneth M. Merz Jr.

  2. Institute for Cyber Enabled Research, Michigan State University, 567 Wilson Road, Room 1440, East Lansing, MI, 48824, USA

    Kenneth M. Merz Jr.

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Song, L.F., Bansal, N., Zheng, Z. et al. Detailed potential of mean force studies on host–guest systems from the SAMPL6 challenge. J Comput Aided Mol Des 32, 1013–1026 (2018). https://doi.org/10.1007/s10822-018-0153-7

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  • DOI: https://doi.org/10.1007/s10822-018-0153-7

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