Overall, SepTop performed well for large scaffold transformations in the BACE dataset. These transformations were challenging or impossible for traditional relative free energy calculations for multiple reasons. Firstly, the maximum common substructure shared by the different ligand scaffolds was very small. In addition, in transformations between the amide series and the two biaryl series, compounds from the amide series extended into the P3 pocket of BACE1 and displaced water molecules that were present in the two biaryl series. These large modifications were captured well in this dataset using SepTop.