When comparing BFE predictions of reference calculations and the EE methods, there is agreement between the approaches. The majority of BFE predictions from these two methods for WP6 systems are within 2 kcal/mol of one another, however, 3 common outliers persist with guests WP6-G1, WP6-G5, and WP6-G8 (Figure ). Major differences between reference calculations and EE approaches are in the microstates of guests and host used, and the sampling technique. From the correlation plots (Figures , 8F, 8G, 8H, and 8I), BFEs for guests G1, G5, and G8 are sensitive to the system set-up and how the guest, or host, or both are modeled. The sensitivity for these systems would suggest some unique molecular recognition characteristics. Another possibility for the BFE inconsistencies can be due to inadequate sampling of the WP6 host, or guests (particularly G1 and G8). In future work, it would be interesting to see if using the same starting structures used in EE methods, if these outliers persist or if there is better agreement with the reference approach.