One exoOA guest posed a bit of a surprise, in that binding of g1 to exoOA was not detected experimentally (Section 6.2 and Figure ). Since no clear evidence of binding was observed experimentally at the detection threshold via ITC or H-NMR, this indicates a binding constant (Ka) to be less than 5 M -1 or a Δ more positive than -0.95. Of the 15 GDCC submissions, 7 predicted this correctly with computed free energies ranging between -0.98 and 6.40 kcal/mol. Of the methods which incorrectly predicted g1 to bind, computed binding free energies ranged from -2.45 to -11.54 kcal/mol. All of the QM based submissions (B2PLYPD3/SMD) predicted exoOA-g1 to be a nonbinder, with values between 2.70 and 6.40 kcal/mol, and the AMOEBA-based alchemical methods also correctly recognized this as a nonbinder. Most MM/PBSA and MM/GBSA submissions failed to recognize this as a nonbinder, except for the RESP/GAFF/MMPBSA/Nmode method utilizing empirical corrections. The other GAFF-based methods predicted exoOA-g1 to be a binder. Predicted binding free energies of xtb-GNF/MachineLearning/CORINA_MD, RESP/GAFF/MMPBSA-Cor, RESP/GAFF/MMGBSA, AM1-BCC/GAFF/MMPBSA, RESP/GAFF/MMPBSA, FSDAM/GAFF2/OPC3, and DOCKING/GAFF/YANK were all more favorable than -3.84 kcal/mol. Perhaps for this guest, the proximal carboxylates of the host and guest repel one another too strongly for binding. This guest has relatively less hydrophobic character than other guests, perhaps meaning that the hydrophobic effect is not enough to offset this potential electrostatic clash. Perhaps only the AMOEBA absolute binding free energy calculations and the QM based methods can capture the relevant polarization effects well enough to recognize this complex is unfavorable.