Our reference calculations encountered particularly severe problems for some host-guest complexes. For example, the TEETOA-G1 prediction for reference calculations was unfavorable at 2.79 kcal/mol, whereas experimentally binding was favorable. In the analysis of the initial simulation the guest leaves the TEETOA pocket, due to the ethyl groups remaining oriented towards the cavity. We tested how the host conformation affected binding by restraining the host ethyl groups to keep them oriented towards the cavity, and found that in this conformation the predicted free energy was 14.87 ± 0.39 kcal/mol. Upon analysis of the new simulation, we observed the guest also leaving the TEETOA cavity, and a poor overlap profile for the attach phase was observed, similar to that of the initial simulation without restraining ethyl groups. In a separate simulation, we restrained all ethyl groups to point away from the cavity resulting in a predicted binding affinity of -1.04 ± 0.54 kcal/mol. Restraining the ethyl groups in the outward orientation improved our overlap profile, guest G1 remained in the TEETOA cavity, improved agreement with experiment, and was in agreement with the similar PMF approach.