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J Comput Aided Mol Des. 2018 Oct;32(10):1047-1058. doi: 10.1007/s10822-018-0154-6. Epub 2018 Aug 29.

Blinded predictions of standard binding free energies: lessons learned from the SAMPL6 challenge.

Author information

1
EaStCHEM School of Chemistry, Joseph Black Building, King's Buildings, Edinburgh, EH9 3FJ, UK.
2
EaStCHEM School of Chemistry, Joseph Black Building, King's Buildings, Edinburgh, EH9 3FJ, UK. mail@julienmichel.net.

Abstract

In the context of the SAMPL6 challenges, series of blinded predictions of standard binding free energies were made with the SOMD software for a dataset of 27 host-guest systems featuring two octa-acids hosts (OA and TEMOA) and a cucurbituril ring (CB8) host. Three different models were used, ModelA computes the free energy of binding based on a double annihilation technique; ModelB additionally takes into account long-range dispersion and standard state corrections; ModelC additionally introduces an empirical correction term derived from a regression analysis of SAMPL5 predictions previously made with SOMD. The performance of each model was evaluated with two different setups; buffer explicitly matches the ionic strength from the binding assays, whereas no-buffer merely neutralizes the host-guest net charge with counter-ions. ModelC/no-buffer shows the lowest mean-unsigned error for the overall dataset (MUE 1.29 < 1.39 < 1.50 kcal mol-1, 95% CI), while explicit modelling of the buffer improves significantly results for the CB8 host only. Correlation with experimental data ranges from excellent for the host TEMOA (R2 0.91 < 0.94 < 0.96), to poor for CB8 (R2 0.04 < 0.12 < 0.23). Further investigations indicate a pronounced dependence of the binding free energies on the modelled ionic strength, and variable reproducibility of the binding free energies between different simulation packages.

KEYWORDS:

Alchemical free energy; Binding free energy; SAMPL6; SAMPLing

PMID:
30159717
DOI:
10.1007/s10822-018-0154-6
[Indexed for MEDLINE]

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