We sought to determine whether some hosts/guests are particularly challenging to predict, across all ranked methods, so we examined the RMSE and ME by host and guest for ranked free energy predictions for all individual host-guest systems. This is shown in Figure . The ranked predictions of all methods for the TrimerTrip/"clip" host-guest systems (shown in blue in Figure ) were in general the most problematic, especially clip-g6, clip-g9, clip-g10, clip-g11, clip-g18, and clip-g19 which had an RMSE of about 4 kcal/mol or greater. All of the guests with an adamantane moiety fall within this list of "problematic" molecules.