For this dataset, good correlation and error statistics were obtained within different scaffold series as well as for transformations across different series. Figure shows the correlation between experimental and calculated binding free energies of the overall dataset. We show correlation both for the raw ∆∆G values of the 45 ligand transformations and the ∆G values of the 18 ligands. Overall, the correlation with experimental data was good with an RMSE of 1.39 kcal mol -1 and an R 2 = 0.71. There were some outliers with larger deviation from experiment both within some of the series as well as for transformations between different series, as can be seen in the correlation of calculated and experimental ∆∆G values, broken up by transformations between and within different series in SI Figure . We found that for this system the ∆∆G values from transformations between ligands within the same scaffold correlated better with experiment than transformations between ligands from different scaffolds (RMSE = 1.07 vs. RMSE = 1.78), which is unsurprising since transformations across scaffolds are clearly more challenging. However, transformations across scaffolds are impossible for standard RBFE calculations, potentially making these transformations still appealing.