Peer review process
Not revised: This Reviewed Preprint includes the authors’ original preprint (without revision), an eLife assessment, public reviews, and a response from the authors (if available).
Read more about eLife’s peer review process.Editors
- Reviewing EditorQiang CuiBoston University, Boston, United States of America
- Senior EditorQiang CuiBoston University, Boston, United States of America
Reviewer #1 (Public Review):
The paper offers some potentially interesting insight into the allosteric communication pathways of the CTFR protein. A mutation to this protein can cause cystic fibrosis and both synthetic and endogenous ligands exert allosteric control of the function of this pivotal enzyme. The current study utilizes Gaussian Network Models (GNMs) of various substrate and mutational states of CFTR to quantify and characterize the role of individual residues in contributing to two main quantities that the authors deem important for allostery: transfer entropy (TE) and cross correlation. I found the TE of the Apo system and the corresponding statistical analysis particularly compelling. I found it difficult, however, to assess the limitations of the chosen model (GNM) and thus the degree of confidence I should have in the results. This mainly stems from a lack of a proposed mechanism by which allostery is achieved in the protein. Proposing a mechanism and presenting logical alternatives in the introduction would greatly benefit this manuscript. It would also allow the authors to place the allosteric mechanism of this protein in the broader context of protein allostery.
Reviewer #2 (Public Review):
In this study, the authors used ANM-LD and GNM-based Transfer Entropy to investigate the allosteric communications network of CFTR. The modeling results are validated with experimental observations. Key residues were identified as pivotal allosteric sources and transducers and may account for disease mutations.
The paper is well written and the results are significant for understanding CFTR biology.
Reviewer #3 (Public Review):
This study of CFTR, its mutants, dynamics, and effects of ATP binding, and drug binding is well written and highly informative. They have employed coarse-grained dynamics that help to interpret the dynamics in useful and highly informative ways. Overall the paper is highly informative and a pleasure to read.
The investigation of the effects of drugs is particularly interesting, but perhaps not fully formed.
