For the unbound part of the thermodynamic cycle, we performed absolute hydration free energy calculations for all neutral ligands. Here, we used 14 λ windows, first turning off the Coulomb interactions and then the vdW interactions of the ligand. For the charged ligands in the BACE1 dataset we ran SepTop calculations (to avoid changing the formal charge of the system 26 ) in the solvent using a total of 28 λ windows (see MDP files in SI for details); essentially, this involved 14 for each ligand.