Dear Mr Bitran,

Thank you very much for submitting your manuscript "DBFOLD: An efficient algorithm for computing folding pathways of complex proteins" 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. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Comments from a prior reviewer are below.  Based on additional review of the manuscript by the editorial team and discussion with reviewers, we have the additional comment and requested revision:

We thank the authors for their changes to the manuscript.  We note that the systems added to the resubmitted manuscript are not novel but have been published by the authors in their prior PNAS paper.  (To be completely forthright, given the advertised computational efficiency of this approach, we would have hoped for additional protein systems.)  Since this makes the paper more a validation study than a new results study, we would suggest that the title be prefixed with "Validation of" to read "Validation of DBFOLD" before the colon.

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Sincerely,

Peter M Kasson

Associate 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: In the revised manuscript the authors have done a good job revising the manuscript that has greatly improved.

I have just a comment about the discussion of protein G vs Protein L folding pathway, which I found a bit too qualitative. The phi-values offer a rather indirect structural information of folding pathways and transition states, and it is possible that the simulation results may actually be consistent with the experiment. To verify this, it would be necessary to compare to the raw data, ie.e folding rates and stabilities of mutants. There are ways to do this. The most accurate would be directly reproducing experimental rates and stabilities by simulation of the mutants, but this is computationally expensive. Alternatively, it may be possible to use approximate methods based on determination of the transition state for folding or of an approximate free energy landscape to infer the effect of mutations on folding rates and stabilities. I am not arguing that the authors must do this at this stage, but it may be worth at least briefly mentioning this point.

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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

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Reviewer #1: Yes: Stefano Piana-Agostinetti

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Dear Mr Bitran,

We are pleased to inform you that your manuscript 'Validation of DBFOLD: An efficient algorithm for computing folding pathways of complex proteins' 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,

Peter M Kasson

Associate Editor

PLOS Computational Biology

Nir Ben-Tal

Deputy Editor

PLOS Computational Biology

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