Affinity grid maps calculations. Grid maps were used to calculate water-protein and water-water interaction energies during the placement and orientation of each individual water molecule. Similarly to what is done for the AutoDock docking protocol, 100 , energy values were obtained by trilinear interpolation of the grid values, providing a significant performance improvement compared to pairwise energy evaluations. Affinity grid maps were calculated with different energy models using AutoGrid4 100 and AutoDock-Vina 1.2 101 . When using AutoGrid4, the AutoDock4 forcefield was replaced with the Amber ff14SB force field 102 to model the protein, ions, if present, and water molecules using the TIP3P water model 103 . When using AutoDock Vina, the standard non-directional, donor-acceptor oxygen probe (O_DA) from the Vina force field was used. Each time a water molecule is accepted, maps are updated by using a pre-calculated single water molecule grid box that is integrated and interpolated into the existing target maps.