Information Transfer in Active States of Human β₂-Adrenergic Receptor via Inter-Rotameric Motions of Loop Regions

Round 1

Reviewer 1 Report

The manuscript describes studying the allosteric communication network in β₂AR bound to Gs using various metrics. I would like to thank the authors for their interesting and thorough work. Overall I find the paper to be of excellent quality, it is very well written and illustrated.

 

I only have some very minor questions and remarks.

1. The “ICL” abbreviation in the abstract and in the beginning of section 3 on page 6 should be explicitly introduces, analogously to the “TM” abbreviation (i.e. intracellular loop (ILC)). The same goes for ECL on page 10 and thereafter.

2. There was a spelling error of “conserved” in the middle paragraph of the Introduction on page 2 (which are mostly conversed among species [9-14]).

3. How did the authors generate the POPC lipid membrane and then embed the protein in it (page 3, section 2)? I recommend adding a reference to the tool they used for this purpose.

4. There is a spelling error in the last paragraph on page 7 – “(3⁶ × 3⁶ × 3⁶ =) 3¹⁸” should be (3⁶ × 3⁶ × 3⁶ = 3¹⁸).

5. As a person that is not too familiar with the β₂AR specifically, I would highly appreciate it if the authors added a short paragraph, describing which residues form the orthosteric binding site and just a very short description of the overall topology of the receptor, may be located somewhere at the beginning of section 3.

6. In regard to the sentence “Despite low MI values observed almost everywhere in the receptor (highest MI = 2.59), the relatively high correspondence between ICL3 and ICL2 regions is noticeable” on page 10, I would like to ask the authors how do they determine if MI values are low or high, is there some accepted threshold? As far as I get it, the range of the MI values depends on the number of degrees of freedom that are included in its calculation?

 

Again, overall the manuscript is well organized, the methods are adequately described and are suitable for the presented problem, the quality of the English language is excellent, and the graphics are useful and of good quality. I highly recommend publication of the manuscript in the Journal Applied Sciences.

Author Response

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

Dear Authors,

Thank you for the opportunity to review the article entitled “Information Transfer in Active States of Human β2-Adrenergic Receptor via Backbone and Side-Chain InterRotameric Motions of Loop Regions”. The article presents a very nice exploration of the motions in the Human β2-Adrenergic Receptor during binding to the associated G-protein using molecular dynamics simulations. The manuscript is very well written, and all data, interpretations, and conclusions are explained clearly. Honestly, I have no further suggestions! It would be nice to see how these conclusions are applicable to other G-protein coupled receptors; however, I understand that this may be out of the scope of the article. It was a pleasure to read this article. One very small note is listed below. Congratulations on the great work. Thank you for your time and consideration.

 

As a personal preference, I suggest the Main Title be something similar to the Short Title, perhaps “Information Transfer in β2AR via Inter-Rotameric Motions of Loop Regions”

Author Response

We thank very much to the reviewer for his/her nice comments about our work. Also, we followed the suggestion and shortened the main title by removing the words "backbone and side-chain". The last updated version was stated as: 

Information Transfer in Active States of Human β₂-Adrenergic Receptor via Inter-Rotameric Motions of Loop Regions