6.4. Molecular shape and chemical similarity may be good metrics for planning SepTop calculations. RBFE calculations, including with SepTop, can be planned more effectively using some measure of ligand "similarity" to assess which transformations will be easy and which will be hard. Here, we have not investigated planning and similarity metrics, reserving for future work. However, it seems likely that SepTop will benefit from different similarity metrics than standard RBFE, since SepTop replaces one ligand with another in the binding site rather than mutating one ligand into the other. In this work we did not explore the impact of the design of the transformation map on the efficiency of the calculations, but we propose that molecular shape and chemical similarity may be good metrics to use for planning SepTop calculation networks, in contrast to the maximum common substructure and 2D graph similarity metrics that are often used in standard RBFE approaches. There is a better chance that ligands introduce similar conformational changes in the protein and that they displace similar water molecules (and therefore converge faster), if the two ligands have a high molecular shape and chemical similarity.