Comparison of the umbrella sampling and the double decoupling method in binding free energy predictions for SAMPL6 octa-acid host-guest challenges.

We calculate the absolute binding free energies of tetra-methylated octa-acids host-guest systems as a part of the SAMPL6 blind challenge (receipt ID vq30p). We employed two different free energy simulation methods, i.e., the umbrella sampling (US) and double decoupling method (DDM). The US method was used with the weighted histogram analysis method (WHAM) (US-WHAM scheme). In the DDM scheme, Hamiltonian replica-exchange method (HREM) was combined with the Bennett acceptance ratio (BAR) (HREM-BAR scheme). We obtained initial binding poses via molecular docking using GalaxyDock-HG program, which is developed for the SAMPL challenge. The root mean square deviation (RMSD) and the mean absolute deviations (MAD) using US-WHAM scheme were 1.33 and 1.02 kcal/mol, respectively. The MAD was the top among all submissions, however the correlation with respect to experiment was unexceptional. While the RMSD and MAD via HREM-BAR scheme were greater than US-WHAM scheme, (i.e., 2.09 and 1.76 kcal/mol), their correlations were slightly better than US-WHAM. The correlation between the two methods was high. Further discussion on the DDM method can be found in a companion paper by Han et al. (receipt ID 3z83m) in the same issue.