From the journal RSC Chemical Biology Peer review history

28-Aug-2023

Dear Dr Nussinov:

Manuscript ID: CB-REV-06-2023-000114
TITLE: Protein conformational ensembles in function: roles and mechanisms

Thank you for your submission to RSC Chemical Biology, published by the Royal Society of Chemistry. I sent your manuscript to reviewers and I have now received their reports which are copied below.

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I look forward to receiving your revised manuscript.

Yours sincerely,
Cai-Guang Yang, Ph.D.
Associate Editor/RSC Chemical Biology
Professor/Shanghai Institute of Materia Medica, CAS
Phone: +86-021-50806029
Email: yangcg@simm.ac.cn

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Reviewer 1

In this timely short review, the authors discussed the importance of considering protein conformational ensembles for understanding function, allostery and disease. The discussions started with a brief discussion of the general relevance of conformational ensembles, and then dived into more detail with several specific and representative examples that highlighted the roles of various post-translational modification, disease-causing mutations and interactions with lipid membrane in shifting the conformational distributions. These discussions support the conceptual framework that describes protein function and regulation in terms of the shifting conformational ensembles, rather than static and rigid structures. Overall, I find the manuscript to be well motivated, clearly written, with excellent up-to-date examples. I support the publication of this contribution in its current form.

Reviewer 2

Shortcomings of the energy landscape concept and the typical sequence-structure-function paradigm are in need of rethinking. This article by Nussinov and colleagues presents a new concept that incorporates conformational ensembles and the population of states to yield the sequence‐conformational ensemble‐function paradigm.

The manuscript could be accepted as is. However, if minor revisions are to be undertaken, two points would be worthy of consideration:
1. It could be helpful, particularly in the section discussing the K-Ras4B G12V mutation, specifically how or why visiting the active state more frequently is important for function.
2. Some sentences could use a small amount of editing for grammar, as some have awkward phrasing or abrupt ending. This is particularly notable in the first paragraph of the section covering Affinity and shift of the ensemble for Raf activation by Ras.

Overall the paper is interesting, of high quality, of good importance, and has good quality and helpful figures.

We thank the referees for the positive comments and appreciation of our Review. Below we address the comments.

** Referee: 1
In this timely short review, the authors discussed the importance of considering protein conformational ensembles for understanding function, allostery and disease. The discussions started with a brief discussion of the general relevance of conformational ensembles, and then dived into more detail with several specific and representative examples that highlighted the roles of various post-translational modification, disease-causing mutations and interactions with lipid membrane in shifting the conformational distributions. These discussions support the conceptual framework that describes protein function and regulation in terms of the shifting conformational ensembles, rather than static and rigid structures. Overall, I find the manuscript to be well motivated, clearly written, with excellent up-to-date examples. I support the publication of this contribution in its current form.
* Our response:
We thank the referee for these comments.

** Referee: 2
Shortcomings of the energy landscape concept and the typical sequence-structure-function paradigm are in need of rethinking. This article by Nussinov and colleagues presents a new concept that incorporates conformational ensembles and the population of states to yield the sequence‐conformational ensemble‐function paradigm.

The manuscript could be accepted as is. However, if minor revisions are to be undertaken, two points would be worthy of consideration:

1. It could be helpful, particularly in the section discussing the K-Ras4B G12V mutation, specifically how or why visiting the active state more frequently is important for function.
* Our response:
We now explained that “Visiting the active state more frequently is important for function since this results in the protein spending more time in the active, here oncogenic, state.”

2. Some sentences could use a small amount of editing for grammar, as some have awkward phrasing or abrupt ending. This is particularly notable in the first paragraph of the section covering Affinity and shift of the ensemble for Raf activation by Ras.
* Our response:
We now slightly touched that paragraph as well.

Overall the paper is interesting, of high quality, of good importance, and has good quality and helpful figures.
* Our response:
We thank the referee for the careful reading of the paper and the comments.

02-Sep-2023

Dear Dr Nussinov:

Manuscript ID: CB-REV-06-2023-000114.R1
TITLE: Protein conformational ensembles in function: roles and mechanisms

Thank you for submitting your revised manuscript to RSC Chemical Biology. I am pleased to accept your manuscript for publication in its current form. I have copied any final comments from the reviewer(s) below.

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With best wishes,

Cai-Guang Yang, Ph.D.
Associate Editor/RSC Chemical Biology
Professor/Shanghai Institute of Materia Medica, CAS
Phone: +86-021-50806029
Email: yangcg@simm.ac.cn

Reviewer 2

Sufficient changes have been made so as to improve the manuscript.