The closest agreement across methods was for WP6-G10, WP6-G3, and WP6-G11, with RMSEs below 2 kcal/mol ( 1.38, 1.79, and 1.84 kcal/mol respectively); while RMSEs on the remaining WP6-guest complexes were between 2 to 4 kcal/mol (Table ). WP6 guests that had the highest RMSE (between 3 to 4 kcal/mol, Table ) were WP6-G13, WP6-G9, WP6-G1, WP6-G12, and WP6-G8. These guests contain an unusual ring system (WP6-G1), adamantane like core (WP6-G9, WP6-G12), or a nitrogen conjugated system (WP6-G13). In SAMPL7 , calculations for Trimer-Trip with adamantane-like molecules (clip-g11, clip-g6, clip-g9, clip-g10) had poor predictive accuracy with RMSE values greater than 4 kcal/mol. In addition, guest clip-g18 from SAMPL7 is the same as guest WP6-G13; this guest contains a nitrogen conjugated system, and had among the highest RMSEs (across methods) of 6.70 and 3.33 kcal/mol, respectively. Thus this particular guest was also challenging in TrimerTrip in SAMPL7. We note that predictive accuracy for SAMPL7 TrimerTrip binding was in general worse, as measured by RMSE. Some participants argued that SAMPL7 was particularly difficult or challenging due to the additional flexibility and poor sampling of the acyclic clip-like host. However, whether the inaccuracies for adamantane-like and nitrogen conjugated system molecules were a result of force field limitations, sampling issues, other environmental factors modeled (buffer conditions, protonation state, etc), or a combination of remains inconclusive, and would require further investigation.