From the journal RSC Chemical Biology Peer review history

25-Jun-2021

Dear Dr Burkart:

Manuscript ID: CB-COM-05-2021-000125
TITLE: Protein-protein Interaction based substrate control in the <i>E. coli </i>octanoic acid transferase LipB

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Claudia Höbartner
Associate Editor, RSC Chemical Biology
Institute of Organic Chemistry, University of Würzburg

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Reviewer 1

All points have been addressed.

Reviewer 2

This is an interesting piece of research that provides an atomic-level explanation for the selectivity of LipB for ACP-bound octanoic acid. The critical protein-protein interactions that confer selectivity are identified by a protocol including NMR titration and molecular docking. In general, the study is well done, the manuscript is clear, and the conclusions are relevant and (partially) well supported by the data. The Achilles' hill of the study is the solid reliance of the results on molecular docking, which is a technique that still faces accuracy limitations. A solid validation of the docking predicting power is needed to provide support to the conclusions.
Fortunately, this is not a too difficult task, as several ACP-protein complexes are available in the PDB, some of which are from FAS systems. Therefore, the authors can benchmark the capacity of the docking protocol in predicting the geometry of these known complexes, ideally in the bound-bound and unbound-unbound form.
The paper might be mostly unchanged by this validation, but I don't feel that the data solidly support the conclusions without it.
The authors should replace "homology" with "sequence identity" in the paper on a final note. Two homologous proteins are two proteins that share a common ancestor. Thus, it is a binary classification- either they share, or they don't, independently of the sequence identity they share.

This text has been copied from the PDF response to reviewers and does not include any figures, images or special characters.

This is an interesting piece of research that provides an atomic-level explanation for the selectivity of LipB for ACP-bound octanoic acid. The critical protein-protein interactions that confer selectivity are identified by a protocol including NMR titration and molecular docking. In general, the study is well done, the manuscript is clear, and the conclusions are relevant and (partially) well supported by the data. The Achilles' hill of the study is the solid reliance of the results on molecular docking, which is a technique that still faces accuracy limitations. A solid validation of the docking predicting power is needed to provide support to the conclusions.
Fortunately, this is not a too difficult task, as several ACP-protein complexes are available in the PDB, some of which are from FAS systems. Therefore, the authors can benchmark the capacity of the docking protocol in predicting the geometry of these known complexes, ideally in the bound-bound and unbound-unbound form.
The paper might be mostly unchanged by this validation, but I don't feel that the data solidly support the conclusions without it.

Response:
We agree that, in isolation, the docking we performed in this manuscript would not be sufficient to recreate the ACP-partner protein interface. However, the development of this methodology was completed in a recent study, now published in Comms. Biol. (ref 23). In that study we developed the methods used here and performed benchmarks of the docking methods on a set of six AcpP-partner protein pairs from the E. coli de novo FAS. This methodology was shown to precisely recapitulate the crystal structure interfaces to below 2 Å RMSD. This analysis is a necessary demonstration of the efficacy of this NMR-guided docking protocol.

In order to make this clearer we have added the following section to the main text, “The methodology used was the same as we previously developed to model six ACP-partner protein interfaces from E. coli FAB and benchmark them with established crystal crosslinked structures 23.”

The authors should replace "homology" with "sequence identity" in the paper on a final note. Two homologous proteins are two proteins that share a common ancestor. Thus, it is a binary classification- either they share, or they don't, independently of the sequence identity they share.

Response: Agreed. We have changed two instances of using “homology” for the term “sequence identity.”

27-Jul-2021

Dear Dr Burkart:

Manuscript ID: CB-COM-05-2021-000125.R1
TITLE: Protein-protein Interaction based substrate control in the <i>E. coli </i>octanoic acid transferase LipB

Thank you for submitting your revised manuscript to RSC Chemical Biology. After considering the changes you have made, I am pleased to accept your manuscript for publication in its current form.

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With best wishes,

Claudia Höbartner
Associate Editor, RSC Chemical Biology
Institute of Organic Chemistry, University of Würzburg