Comparing predictions of APR/GAFF2-AM1BCC/TIP3P/US/TI (reference calculations) with the top performing PMF/GAFF2-AM1BCC/TIP3P/MD-US method also using GAFF2, we observe an RMS difference of 2.97 and kcal/mol for TEMOA and 3.32 kcal/mol for TEETOA. As indicated by these RMS differences, the predictions of the two methods indeed vary more for TEETOA systems (for 4 of 5 guests, predictions differ by at least 2 kcal/mol). One way in which the methods differ is that in reference calculations conformational restraints were applied on the TEETOA host cavity, so the fact that these methods yield different results suggests a binding mechanism involving TEETOA conformational change(s), likely of the ethyl side chains. In addition, the methods differed in their computed binding free energies for TEMOA-G2 and TEMOA-G3 by more than 4 kcal/mol in each case, while the remaining systems (TEMOA-G1, TEMOA-G4, and TEMOA-G5) were all within 0.13 kcal/mol of one another. The discrepancy for TEMOA-G2 is likely due to modeling differences of G2, where the reference had a deprotonated (charged) hydroxyl while in the PMF approach the hydroxyl was protonated (neutral). The use of conformational restraints of TEMOA may play a role rendering G3 particularly sensitive to this, though the reason for the discrepancy between TEMOA-G3 predictions with these two methods is not obvious.