The ligand-protein systems used in this study are comprised of some selected benchmark sets that have already been studied with FEP+. This dataset covers a wide range of ligands and target classes (305 ligands and 14 protein targets). We studied 503 ligand perturbations that include a wide range of chemical modifications typically seen in medicinal chemistry efforts. Out of the 14 protein systems studied here, 8 were part of the previous FEP+ study by Wang et Galectin 53 and three additional BACE datasets. In addition, all of these systems except BACE (scaffold) were also studied using a non-equilibrium alchemical approach referred to as "PMX" hereafter in this article.