As shown in Figure , there were 7 host-guest systems in SAMPL8 which had RMSE of about 4 kcal/mol or greater. Of these, indeed the majority of the molecules with the lowest accuracy (CB8-G4, CB8-G7, CB8-G3, CB8-G6, and CB8-G1) were in the CB8 dataset. The majority of methods tended to predict binding free energies for these systems to be less favorable, and the largest ΔΔ errors were more than 8 kcal/mol too favorable (Figure ). Guests G3 (morphine), G4 (hydromorphone), and G7 (cocaine)