In the case of binding enthalpies (Figure ), SMIRNOFF99Frosst agrees the best with experiment (RMSE ). All force fields perform poorly at replicating -TΔS° for carboxylate guests, with RMSEs ranging from 1.8 [0.7, 3.2] kcal/mol (GAFF v2.1) to 3.0 [2.1, 3.9] kcal/mol (GAFF v1.7). All force fields also underestimate the entropic component of binding of a-coc (αCD:cyclooctanol) relative to experiment, by 3-5 kcal/mol. This is likely due to the poor fit of cycloctanol inside the cavity of αCD, particularly in the primary orientation (Figure ). Overall, SMIRNOFF99Frosst and GAFF v1. Analysis of the simulations with MBAR produces very slightly improved results for SMIRNOFF99Frosst ΔG°, ΔH, and -TΔS° compared to experiment (Table ), but they do not appear to be statistically significant.