Dear Arne,

Thank you very much for submitting your manuscript "Accurate contact-based modelling of repeat proteins predicts the structure of new repeats protein families." for consideration at PLOS Computational Biology.

As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

Two reviewers felt that the manuscript did not contain the amount of new methodological innovation expected of a PLoS Computational Biology article. Reviewer 2 suggested to include distances predicted by RaptorX-Contact to the evaluation. As such, the paper would earn its merits more as a benchmarking study, which seems to make sense, given that you have already included constraints from two different contact prediction methods. (If there are additional distance/contact predictors that can be included, it makes sense to include these too.) If you can add this analysis, we would be interested to receive a revision. We are sorry to not be able to be more positive at this point. 

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Johannes Soeding, Ph.D.

Guest Editor

PLOS Computational Biology

Nir Ben-Tal

Deputy Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The paper deals with an interesting and novel aspect of protein feature predictions. The authors took into considerations all the major criticisms raised by reviewers and edited the paper accordingly. The problem of redundancy is now correctly described.

Reviewer #2: The authors did some modifications of the manuscript by testing the contacts predicted by DeepMetaPSICOV and developing a random forest regression method to predict the quality of a 3D model. However, the authors did not test folding of distance (and orientation information used by trRosetta). It is unclear why the authors did not test the distance (and orientation) information predicted by RaptorX-Contact simply because it is a web server. In fact, it is much more convenient to use a web server than a standalone software package. A hassle-free strategy is to submit the test proteins to the RaptorX-Contact web server and then evaluate the contact/distance prediction and 3D models returned by the server. Overall, this manuscript represents a simple application of existing (but not very cutting-edge) techniques to an interesting problem. As a proof of concept, it may be sufficient, but it may not represent what we can do on the modeling of repeat proteins using existing techniques and tools.

Reviewer #3: I find that the paper does not features works of 'exceptional significance', but a specific evaluation of distinct methods to asses a specific technical question. The exceptional significance would be if the paper fully describe and asses novel structures for repeat proteins based on these findings, but I that this is lacking in the manuscript.

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Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #1: Yes

Reviewer #2: None

Reviewer #3: None

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PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

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Dear Arne,

We are pleased to inform you that your manuscript 'Accurate contact-based modelling of repeat proteins predicts the structure of new repeats protein families.' has been provisionally accepted for publication in PLOS Computational Biology.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology. 

Best regards,

Johannes Soeding, Ph.D.

Guest Editor

PLOS Computational Biology

Nir Ben-Tal

Deputy Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #2: The authors have applied trRosetta to their proteins and improved the results, and I think now the work is ready for publication.

By the way, in CASP14 Baker's trRosetta worked better than RaptorX mainly because the former used very large metagenome databases to generate MSAs while the latter does not, which is very important in CASP14 since it has quite a few test targets (from the same complex) that need metagenome data. Nevertheless the authors do not seem to use any metagenome data in this manuscript. The whole RaptorX package is also publicly available at https://github.com/j3xugit/RaptorX-3DModeling for local installation.

Reviewer #3: ok

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Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #2: None

Reviewer #3: Yes

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PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: No