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

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 ( CB 8) 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 (R 2 0.91 <0.94 <0.96), to poor for CB8 (R 2 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.