where E i and p i are the energy and the probability associated to the orientation i, respectively, and M the total number of orientations sampled (9897 orientations). Finally, only the E n value is stored in the grid map, while no directional information is conserved. Spherical map using AutoDock-Vina Another spherical map was calculated using the O_DA atomic probe, which defines a non-directional donor-acceptor oxygen in the AutoDock Vina empirical force field 104 . The force field includes a van der Waals-like potential (a combination of two attractive gaussian terms and a repulsion term), a non-directional linear hydrogen-bond term, a hydrophobic term, and no electrostatic term. Due to the lack of directionality for both donor and acceptor hydrogen bond terms, the O_DA probe is not affected by the position of explicit polar hydrogen atoms in the target structure (Fig. ). This provides a clear advantage when sampling interactions around residues with disordered hydrogens such as those in hydroxyl (Ser, Thr, Tyr), thiol (Cys), and protonated amine groups (Lys, N-terminus). One potential downside is the complete lack of directionality also for the donors. This grid map was calculated using AutoDock-Vina 1.2 101 . Grid map parameters For all targets, cubic grid boxes were centered on the ligand binding sites of interest, and their size set to 65 x 65 x 65 points, using the default grid spacing of 0.375 Å (resulting in 24.375 Å-side cubes). The default AutoGrid4 smoothing factor was disabled, and the dielectric constant was set to 1.