In at least one case, the origin of method differences is clear. In particular, several different free energy methods used OpenFF 2.0.0 and largely agreed with one another, except for three hostguest combinations (WP6-G1, WP6-G5, and WP6-G8; Figure ). In these specific cases, the methods -which should give equivalent results given the same model, setup, and enough simulation time -agree for all host-guest combinations except these three. For these three, they disagree at least in part because participants selected different protonation states for the host and/or guest for these specific complexes. Here, these discrepancies show the sensitivity of predicted BFEs to the chosen microstate(s) (specifically, protonation state) for the guest or host and help identify the likely dominant bound state(s). In addition, guests WP6-G1 and WP6-G8 have greater flexibility, thus differences or inadequate sampling of conformational space between the methods may have contributed, especially as protonation states were varied. .