A different ( DDM/FEP/MBAR/ParamChem) generated CGenFF parameters for each host-guest system via the ParamChem webserver. BFEs for all bCD systems were estimated to be too favorable by 2.0 to 4.0 kcal/mol; and all HbCD systems were estimated to be too unfavorable by 3.0 to 4.5 kcal/mol. Both the CGenFF and 53A6 GLYC models' statistical performance was similar relative to one another and to that of reference calculations. In other words, the choice of CGenFF parameters did not result in a significant difference in predictive power overall. However, a closer look at BFE predictions with 53A6 GLYC ( DD/GROMOS-53A6_glyc/SPC/MD) for specific systems compared to experiment shows instances where on one hand mod-eling a dominant binding mode had considerable success and on the other hand poorly predicted BFEs where predicted binding free energies seem to err in a way consistent with the use of an incorrect or non-dominant binding mode.