System preparation. The crystallographic structures of the targets were all prepared using CHARMM-GUI 105 . All nonstandard residues (including ligands) and crystallographic water molecules were removed, while ions were kept. Receptors were modeled using Amber ff14SB forcefield. Missing N-and C-terminal parts were not reconstructed and charged N-and C-terminal patches were applied according to the standard Amber protocols. Disulfide bridges patches were also applied when necessary. For hivpr, the side chain of Asp25 in all chains B (PDB ids: 2zye, 1hpx) was modeled in the neutral form (Amber residue nomenclature: ASH) 96, . For all other systems, all aspartate and glutamate side chains were modeled in the deprotonated (negatively charged) form, while lysine and arginine sidechains were modeled as protonated (positively charged). Histidine residues were protonated on the Nδ position (Amber residue nomenclature: HID). Finally, each system was build using the tleap module in the Amber package. Protein targets were placed in an orthorhombic box sized such that faces were placed at 14 Å from the closest protein atom, and solvated with explicit TIP3P water molecules. The water box was placed using the solvatebox command with a closeness of 0.5, instead of 1.0, in order to accelerate the diffusion of water molecules inside the ligand binding pockets. To neutralize charges, Na+/Cl-counter-ions were added avoiding the binding site volume to prevent perturbing water molecules placement.