We totally agree with the referee that also mutations at a greater distance may affect the binding pocket under spe-cial circumstances and we have added a new paragraph to the manuscript. However, we have to admit that it remains essentially impossible to quantify the influence of non-direct interactions by theoretical means unambiguously. In our experience, co-evolution measures such as the one proposed and several others (PMID: 18056067) produce high rates of false positives and, therefore, the interpretation is difficult. We did the requested analysis with Ranganathan's SCA algorithm to eventually identify connected networks of residues using the webserver implementation at the Gerstein lab, but no network that would connect the surface directly to the core and catalytic site was found (see supplementary webpage for full details). 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. A possible problem why the SCA could not work in this case is the high level of sequence similarity among the neuraminidases which only gives limited numbers of informative correlated mutations. This is a totally different scenario from alignments of highly divergent sequences that still have the same fold, such as the small PDZ domains analyzed by Ranganathan. In the case of a diverse family with shared fold, correlated mutations are indicative of allowed fluctuations also among structurally important residues. However, with the neuraminidases, most variation can be attributed to surface residues, which makes sense given the pressure to avoid immune responses. Additionally, sequence sampling of neuraminidases is not independent but biased by transmission chains and clusters of outbreaks. A possible but also not necessarily more precise alternative to judge indirect effects on drug binding would be to run free energy simulations with the bound drug to judge changes of affinity caused by the mutations but this is a tricky and time-consuming endeavour that would burst the scope of this current manuscript.