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 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<1.50kcalmol(-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.