It has to be noted that indirect effects of the mutations that may alter the binding pocket also from a greater distance are difficult to assess and cannot be excluded. To this extent, we have analysed coevolution patterns in an extensive alignment of more than 6000 non-identical Influenza A neuraminidases to eventually identify connected networks of residues using the SCA algorithm [38] as implemented in [39] , but no network that would connect the surface directly to the core and catalytic site was found (see supplementary material). In fact, all positions of the observed mutations are at the surface and naturally variable, as judged by the conservation and SCA analysis, which would rather indicate that they do not have an effect on the structure of the more distant binding pocket.