CGenFF/MATCH* Small molecule parameterization with the CGenFF 59 force field was performed by assigning atom types with the MATCH 60 tool and subsequently replacing the bonded-parameters with those in CGenFF v3.0.1. For the BACE inhibitor sets, the MATCH algorithm was unable to identify the appropriate atom types, therefore in these cases a web-based atom-typing and parameter assignment server was used in combination with the CGenFF v4.1 parameters. As for GAFF2.1x above, virtual charged sites were added to chlorine and bromine containing ligands. Throughout the manuscript we refer to this parameterization as CGenFF/MATCH* to mark that a several different tools were employed in the parameterization procedure which may lead to differences in assigned parameters depending on the atom-typing, generalized force field version and even structure converter used. OPLS3e The Schrodinger force field OPLS3 and OPLS3e 50 was used in the FEP+ results presented, which were taken from published sources. Table .1 lists the source of the results for each target. For simplicity, we labelled all the FEP+ results in the plots and tables as "OPLS3e".