where CC j is the cycle closure of cycle j and n is the number of edges in cycle j. For the cycle closure analysis, we considered the entire ligand dataset, including the compounds with measured binding affinities outside the assay limit. Ligand cycles were enumerated using functions from the NetworkX package 62 which were modified by prior authors 63 to handle this problem. Most of the ligand cycles (51/87) had a cycle closure below 0.5 kcal/mol, however, for 6 ligand cycles, the cycle closure was above 1 kcal/mol, indicating sampling problems (see SI Figure ).