Va et al. Biology Direct (2015) ten:Page 25 oflength is “washing out” the variations inside the population of salt bridges. The `cutoff of 8-12A or even longer’ described by the Reviewer, may be connected not to salt bridges per se but to “longer range ion pairs” (as defined by Nussinov and co-workers, see [50, 51]). We weren’t interested in such weak interactions given that they have been unlikely to contribute to triggering a major rearrangement of your WD-7 domain of Apaf-1 upon the binding of cytochrome c. As for electrostatics interactions in general, for MD simulations we utilised a 10 cut-off for coulombic interactions and 14 cut-off for all long-distance interactions with mixture of PME in addition to a switch function for the direct-space portion. 29) The story about “..angle between the C atoms..” is superior left out. It weakens the story. There is no sensible justification for this that I can assume of that doesn’t automatically goes with the wash in MD. Authors’ response: We would ACVR2A Inhibitors medchemexpress rather leave this part in since the cooperativity with the BZ-55 custom synthesis complex salt bridges, which is determined not by the exact nature in the lysine residue, but by the neighboring position with the two aspartate residues, could be essential for triggering the rearrangement of Apaf-1.. 30) Any sentence that starts with “..As currently noted..” can be deleted. Here as well. We would rather maintain it since it is usually a reference to prior operate. 31) If lysines raise (evolutionary) in the a single side with the binding interface, then what in regards to the unfavorable charges in the other side Authors’ response: We now address this point inside the second part of the’Sequence analysis’ section and inside the Discussion section of your revised manuscript. 32) The discussion is a lot of a repeat from the preceding, and not sufficient a discussion. Authors’ response: Within the revised manuscript, we deleted the repeats (at least, some) and have substantially expanded the Discussion. 33) In Fig. three I would have loved to see how properly the electrostatic potentials around the two proteins thatare docked fit, or how properly points cancel out, or anything like that. Immediately after all, nature wants items to become neutral. Authors’ response: We have modified Fig. three (Fig. 4 within the revised manuscript) to illustrate the electrostatic complementarity. 34) Is Fig. four truly necessary Authors’ response: Figure four is now the Figure 1 with the revised manuscript. It’s a comparison of the PatchDock’ model (this perform) with the previously published model structure by Yuan et al. [PDB:3J2T] [25]. Both models are fitted into experimental cryo-EM density map [24]. We feel that this figure is helpful, since it illustrates that the proposed PatchDock’ model matches the cryo-EM data. 35) Figures 8 and 9 nicely indicate the sequence patterns, but there’s so much distraction that they just about make it harder as an alternative to simpler to find out issues. Authors’ response: We employed the Sequence Logo representation [89], a well known tool for illustrating various alignments of substantial numbers of sequences, for these figures (Figs. 9 and 10 in the revised manuscript). In a such presentation, the statistical significance in each position is cseen. In the revised manuscript, we also add a multiple alignment of your WD domains as Additional file 1: Figure S2. In summary, I feel this is a uncomplicated study that mainly got complicated by the enormous size of the complicated at hand. I indicated one error that really should be fixed. I would really like to see how their final model fits within the EM density, and I miss a bit the experimental valid.
