Our reference calculations (Docking/GAFF/YANK_REF performed reasonably well for this dataset (Table ), and surprisingly had better correlation to experiments compared to other methods (Table ). Predicted binding free energies were within 2 kcal/mol for 9 of 16 host-guest systems, and similar conditions and water model were used as for Noneq/Alchemy/GAFF, though different free energy estimation techniques were used. These submissions also differed in handling of binding modes; our reference calculations used only a single initial binding mode for each (determined by the top scoring pose from docking) whereas Noneq/Alchemy/consensus considered up to two poses whenever a second orientation was considered stable and was in better agreement with experiments. Thus, suggesting secondary guests orientations may need to be considered, and guest and/or host side chain sampling may be an issue.