supported by the ABFE results (SI Table ). The large activity cliffs seen in these merging decisions, often exceeding 5 kcal/mol, are easily captured by the ABFE simulations even in cases where uncertainty exceeds 1 kcal/mol. The only miscalculated merging decision involves a relatively small ΔΔG change of 0.64 kcal/mol in experimental affinities (ligand 2 to ligand 16), which is miscalculated through ABFE by 3 kcal/mol in the opposite direction.