Va et al. Biology Direct (2015) ten:Web page 25 oflength is “washing out” the variations in the population of salt bridges. The `cutoff of 8-12A and even longer’ pointed out by the Reviewer, could be related to not salt bridges per se but to “longer variety ion pairs” (as defined by Nussinov and co-workers, see [50, 51]). We weren’t thinking about such weak interactions due to the fact they were unlikely to contribute to triggering a significant rearrangement with the WD-7 domain of Apaf-1 upon the binding of cytochrome c. As for electrostatics interactions generally, for MD simulations we applied a 10 cut-off for coulombic interactions and 14 cut-off for all long-distance interactions with mixture of PME and a switch function for the direct-space aspect. 29) The story about “..angle amongst the C atoms..” is greater left out. It weakens the story. There is no sensible justification for this that I can assume of that doesn’t automatically goes together with the wash in MD. Authors’ response: We would rather leave this component in since the cooperativity from the complicated salt bridges, that is determined not by the precise nature from the lysine residue, but by the neighboring position in the two aspartate residues, may be significant for triggering the rearrangement of Apaf-1.. 30) Any sentence that begins with “..As already noted..” could be deleted. Right here too. We would rather preserve it because it is really a reference to prior operate. 31) If lysines increase (evolutionary) at the one side of the binding interface, then what in regards to the damaging charges in the other side Authors’ response: We now address this point within the second portion of the’Sequence analysis’ section and inside the Discussion section of your revised manuscript. 32) The discussion is too much a repeat of the preceding, and not sufficient a discussion. Authors’ response: Inside the revised manuscript, we deleted the repeats (at the very least, some) and have substantially expanded the Discussion. 33) In Fig. 3 I’d have loved to view how nicely the electrostatic potentials about the two proteins thatare docked fit, or how nicely items cancel out, or a thing like that. After all, nature desires factors to be neutral. Authors’ response: We’ve modified Fig. three (Fig. 4 inside the revised manuscript) to illustrate the electrostatic complementarity. 34) Is Fig. 4 seriously necessary Authors’ response: Figure 4 is now the Figure 1 of your revised manuscript. It is a comparison of your PatchDock’ model (this function) using the previously published model structure by Yuan et al. [PDB:3J2T] [25]. Each models are fitted into experimental cryo-EM density map [24]. We think that this figure is beneficial, because it Acid Yellow 36 Cancer illustrates that the proposed PatchDock’ model matches the cryo-EM data. 35) Figures eight and 9 nicely indicate the sequence patterns, but there is certainly so much distraction that they practically make it harder as opposed to easier to view items. Authors’ response: We utilised the Sequence Logo representation [89], a popular tool for illustrating a number of alignments of massive numbers of sequences, for these figures (Figs. 9 and ten within the revised manuscript). In a such presentation, the statistical significance in every position is cseen. Within the revised manuscript, we also add a several alignment in the WD domains as More file 1: Figure S2. In summary, I think this is a uncomplicated study that mainly got difficult by the enormous size in the complex at hand. I indicated 1 error that really should be fixed. I would like to find out how their final model fits in the EM density, and I miss a bit the experimental valid.