In contrast, binding free energy calculations had greater errors for guests G1 and G5 in the presence of the TEETOA host (Figure ). Meanwhile, between the two guests, errors were larger for G1 compared to G5. We speculate this may be due to the rearrangement of the ethyl groups at the cavity entrance. Particularly, we could expect the ethyl group rearrangement to be of greater importance for TEETOA-G1, since G1 is larger and would likely require (more of) the ethyl substituents to point away from the cavity for binding. The lack of host conformational sampling and the free energy contribution associated with the particular conformation(s) rearrangement(s) is not considered in the binding free energy prediction, hence the inaccuracy.