The average number of water molecules inside the pocket was calculated by setting up an "atomic cage" defined by the C α of the eleven binding residues PHE115, GLU173, SER174, PHE175, TYR218, THR220, PHE223 (in the principal subunit) and PHE79, ARG81, LEU133, SER145 (in the complementary subunit). The ConvexHull package from SciPy was utilised to check if the oxygen atoms of water molecules were located inside the cage, which was updated at each MD frame. The volume of the ConvexHull was also cal-culated as an estimation of pocket expansion. Pocket volumes were also examined with the software MDPocket. To describe the orientation of Loop C, the loop that caps the binding site, we measured the angle (shown in in Figure ) defined by the center of mass of the C α of the three pairs of residues describing: the apex of Loop C (residues ASN219 and THR220, indicated with the letter C in Figure ), its hinge (THR215 and THR224, indicated with O), and a reference point in the complementary subunit (ASN58 and ARG81, indicated with G). This angle has the advantage of considering only the bending of Loop C, disregarding other factors, e.g.