From the discussion above, it is apparent that establishing unambiguously the nature of cooperation (especially NC) may be highly non-trivial. This is the case of the SARS-CoV-2 main protease (Mpro hereafter) , a fundamental target against the virus . This enzyme is active only as a homodimer , with the N-finger of one monomer shaping the substrate-binding site of the other 26 (Fig. ). This suggests a cooperation between the binding sites . However, the type of cooperativity has not been unambiguously demonstrated. From one hand, PC has been suggested by the following facts: (i) HC is greater than 1 , however this could be caused by the fact that most of its ligand are covalent binders, as well as by the fact that ligand binding might not be simultaneous . (ii) Almost all of the ligand/protein complexes solved by macromolecular X-ray crystallography (MX) contain two ligands per dimer (as shown by an inspection of the 500 structures in the PDB DataBank (, Tab. 1 in Methods) , (iii) the apo-Mpro and almost all (99%) of the ligand/Mpro complex MX structures exhibit dimeric symmetry. However, these facts could be the consequence of the excess of ligands added in the crystallization procedure (saturating both active sites) that might in turn cause the protein to crystallize as a homodimer with only one monomer in the asymmetric unit (See Methods for details).