We picked three ligands binding to tyrosine kinase 2 (TYK2) as a first test system. Those three ligands were structurally very similar and differ by small R-group changes (Figure ). This allowed us to compare SepTop to standard RBFE making this system a good sanity check to ensure that the method is giving correct results. Using the same input structures and force field parameters from a previous study, the ∆∆G values of different RBFE methods should converge to the same result within statistical uncertainty.