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Blinded Predictions of Standard Binding Free Energies: Lessons Learned from the SAMPL6 Challenge

preprint
revised on 15.08.2018 and posted on 16.08.2018 by Michail Papadourakis, Stefano Bosisio, Julien Michel

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 cucuribituril 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.

History

Email Address of Submitting Author

julien.michel@ed.ac.uk

Institution

University of Edinburgh

Country

United Kingdom

ORCID For Submitting Author

0000-0003-0360-1760

Declaration of Conflict of Interest

no conflict of interest

Version Notes

version 2 15/08/2018

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