On the other hand, binding free energy predictions for G1 and G5 with TEMOA were more accurate. G1 and G5 are more amphipathic, with a single polar end, a carboxylic acid, and the other end being strictly hydrophobic. The hydrophobic end is buried in the cavity interacting with the host. The carboxylic acid points away from the cavity and interacts with the bulk solvent and not with waters in the TEMOA cavity upon binding. Compared to G2 and G4, the amphiphilic character of G1 and G5 could explain the higher predictive accuracy for these systems even without explicitly modeling polarizing effects.