For all methods where a single binding mode was used and with reference calculations that considered two binding modes, the models have RMSE and MAE values higher than 3 kcal/mol. In some cases, it is true that using only the most favorable binding mode (which contributes the most to the overall BFE) and ignoring other binding modes yields accurate predictions and incurs only small and negligible errors. However, the most favorable binding mode cannot necessarily be predicted a priori making this strategy often impractical. The SAMPL9 bCD dataset results showcases instances where predictions can be accurate even without considering additional binding modes, and instances where that is not the case, highlighting the remaining importance of methods for binding pose selection and thus binding mode prediction and/or sampling of binding modes.