Some of the methods are physics-based and attempt to calculate true binding free energies. In theory, such methods (when using the same underlying energy model) should give consistent predictions even if the details of the approach are somewhat different. However, in practice this has not always been the case. Indeed, after surveying the predicted binding free energies for WP6-guest systems we find that predictions for the same hostguest complex varied between methods, in some cases the absolute DDG error had a range of nearly 10 kcal/mol (Figure †), illustrating predictive variability across methods for most WP6 systems. This observation remains true for the dataset when we consider non-ranked approaches as well, thus a total of 12 methods. For example, WP6-G8 complex had the highest RMSE of 3.94 kcal/mol, and may not come as a surprise for methods using generalized force fields since the guest contains a sulfonate group (Figure ). Development and/or optimization of parameters for sulfur containing small molecules have been ongoing work for small molecule force fields. These results hint towards force field limitations and/or inaccuracies, but other factors such as sampling, solvent effects, or buffer effects can't be eliminated.