For transformations between ligands in the same scaffold series in the BACE system, Sep-Top achieved an RMSE of 1.07 kcal mol -1 . Two of the three series (the amide series and the spirocyclic series) have been studied using standard RBFE approaches. Those studies treated the different ligand series separately and reported an RMSE of around 1 kcal mol -1 on each. Thus, on this BACE system, SepTop achieved a performance comparable to prior studies, however, this is the first study that carried out transformations spanning across these distinct chemical series, possible here because our approach is more general.