Dear Dr. Baker,

Thank you very much for submitting your manuscript "Fast and versatile sequence-independent protein docking for nanomaterials design using RPXDock" 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.

We are in agreement with the reviewers that this is important work. We are also in agreement with the reviewer that the manuscript would be much clearer with some example of an application. Though we understand that many applications would be publishable in their own right, we hope there is something that could illustrate RPXDock usage.

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,

Joanna Slusky, Ph.D.

Academic Editor

PLOS Computational Biology

Lucy Houghton

Staff

PLOS Computational Biology

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I am in agreement with the reviewers that this is important work. I am also in agreement with the reviewer that the manuscript would be much clearer with some example of an application. Though I understand that many applications would be publishable in their own right, I hope there is something that could illustrate RPXDock usage.

Reviewer's Responses to Questions

Comments to the Authors:

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

Reviewer #1: The paper describes a new computational procedure for docking proteins into user-defined oligomeric symmetries. A number of techniques addressing this problem have been developed by others. However, the procedure described in the paper emphasizes flexibility of its application to a variety of tasks, and utility for the practical use in protein design, including completeness of user's documentation, accessibility to the users community, etc. The procedure is properly benchmarked and described in great detail. As such it should be a useful addition to the toolchest of protein design community.

A small technical glitch - Supplemental Figure S1 is placed in the main text, instead of the Supplement.

Reviewer #2: This paper is the description of RPXDock, a software package for sequence-independent rigid-body protein docking across a wide range of symmetric architectures, suitable for large constructs of 1 or 2 types of proteins towards desired configurations. The software is novel and potentially very useful.

However, I consider it a problem that while the description of the methods and use options is complete and very detailed, there is not a single example demonstrating the use of the software. I think this is a missing component. The paper states that “RPXDock was used to successfully design cyclic oligomers (Gerben et al., submitted), one-component nanocages (Wang et al. 2022), two-component nanocages (Li et al., submitted; Huddy et al., in preparation; Dosey et al., in preparation), and even larger pseudo-symmetric nanomaterials (Dowling et al., in preparation; Lee et al., in preparation), establishing its utility and generality.” Thus, the only paper currently available is Wang et al. “Improving the Secretion of Designed Protein Assemblies through Negative Design of Cryptic Transmembrane Domains.” in preprint, and it focuses on the analysis of the designed assemblies rather than on their design. All the other paper are submitted or in preparation, and do not demonstrate the methodology. Thus, the performance of the method can be fully understood only by downloading and installing the software, which makes it difficult to form an informed opinion. I understand that the authors may want to publish the methodology prior to application papers, but I think including some demonstration of results would make this paper more interesting to readers.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data and code should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: No

Reviewer #2: 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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Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Dear Dr. Baker,

Thank you very much for submitting your manuscript "Fast and versatile sequence-independent protein docking for nanomaterials design using RPXDock" for consideration at PLOS Computational Biology.

Your manuscript was reviewed by members of the editorial board.  We would like to invite the resubmission of a significantly-revised version that takes into account the following concerns:

The experimental validation provided is extremely impressive and illustrate well the functionality of the algorithm. However, more detail needs to be provided for how the experimental validation was preformed  for usability/reproducibility.  Please include details of:

1) what proteins were used 

2) which parts of the protein were redesigned using Rosetta or ProteinMPNN

3) which of those two methods was used for each protein

and 4) the parameters that were used in each case. 

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,

Joanna Slusky, Ph.D.

Academic Editor

PLOS Computational Biology

Nir Ben-Tal

Section Editor

PLOS Computational Biology

***********************

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.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example in PLOS Biology see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Dear Dr. Baker,

We are pleased to inform you that your manuscript 'Fast and versatile sequence-independent protein docking for nanomaterials design using RPXDock' 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,

Joanna Slusky, Ph.D.

Academic Editor

PLOS Computational Biology

Nir Ben-Tal

Section Editor

PLOS Computational Biology

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