Assessing interface accuracy in macromolecular complexes

Olgierd Ludwiczak; Maciej Antczak; Marta Szachniuk

doi:10.1371/journal.pone.0319917

Peer Review History

Original SubmissionNovember 20, 2024
20 Nov 2024 Author Response Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. https://doi.org/10.1371/journal.pone.0319917.r001
15 Dec 2024 Decision Letter - Yong Wang, Editor PONE-D-24-53421The I-INF metric for assessing the quality of macromolecular assembly predictionPLOS ONE Dear Dr. Szachniuk, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== The reviews highlight both the potential utility of I-INF and several significant concerns regarding its novelty, theoretical foundation, and applicability. While one reviewer expressed overall satisfaction, their sole recommendation—a comparative figure—should be considered alongside the more extensive issues raised by the other reviewer. The manuscript provides a valuable contribution to the evaluation of structural prediction methods. However, addressing the outlined deficiencies is essential to ensure the robustness, usability, and contextual grounding of I-INF as a broadly applicable metric. ============================== Please submit your revised manuscript by Jan 29 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. 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Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data 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 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—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This manuscript describes I-INF, a metric to evaluate the correctness of inter-molecular hydrogen bonding. Both the code and the manuscript is overly simple. Major issues include: 1. Hydrogen bonding evaluation is routinely done in CASP, e.g., in https://pmc.ncbi.nlm.nih.gov/articles/PMC4282348/, except that I-INF takes the geometric average while CASP uses harmonic average. Please properly credit earlier works and explain the differences. 2. TM-score an I-INF does NOT measure the same aspect of complex assembly. I-INF only evaluate the correctness of interface, while TM-score evaluates the global topology. There should be some theoretical justification on why TM-score has a high correlation with I-INF. 3. The title strongly suggest that I-INF works even for any bio-macromolecular complexes including pure protein complexes. However, all evaluations in the result section are on protein-RNA complexes. There should be some application of I-INF on protein-protein complexes or explanation on why this is not applicable. 4. A major challenge in complex assembly evaluation is symmetric. For example, suppose the input is a tetramer containing two identical copies of a protein and two identical copies of an RNA, where the two RNA chains interact with each other. In this case, deriving a correct chain mapping for optimal I-INF is not trivial. This work simply ignore this challenge by forcing the user to input consistent chain ID mapping. This makes the program less useful. 5. There is no support for mmCIF format, which is particularly relevant for this work which is supposed to work with large complexes with >65 chains. Reviewer #2: This work studies the evaluation of 3D structural prediction for macromolecular complexes, which is an essential problem in understanding cellular functions. The authors propose a novel metric, I-INF (Intermolecular Interaction Network Fidelity), to quantitatively assess the intermolecular interactions within multichain complexes. This manuscript is very well written and the I-INF score is useful. And I have only one minor comment about it. When comparing I-INF with existing methods such as TM-score and DockQv2, it is recommended to add a figure to make the comparison more clear. ****** 6. 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? 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Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0319917.r002
Revision 1
29 Jan 2025 Author Response We thank the Reviewers for all the comments and suggestions. We responded to them to the best of our ability and made the required changes to the manuscript. In line with PLOS ONE recommendations, we integrated the Zenodo platform with our tool repository on GitHub, enabling us to assign a unique DOI for each new release. The current DOI for the I-INF tool (version 1.0) is 10.5281/zenodo.14697284, and it can be accessed via https://zenodo.org/records/14697284 or https://dx.doi.org/10.5281/zenodo.14697284. All future updates will also be made available through these links. Reviewer 1 This manuscript describes I-INF, a metric to evaluate the correctness of inter-molecular hydrogen bonding. Both the code and the manuscript is overly simple. Major issues include: {Comment 1:} Hydrogen bonding evaluation is routinely done in CASP, e.g., in https://pmc.ncbi.nlm.nih.gov/articles/PMC4282348/, except that I-INF takes the geometric average while CASP uses harmonic average. Please properly credit earlier works and explain the differences. {Response:} We thank the Reviewer for highlighting the evaluation approach used in CASP, particularly the application of the harmonic mean (e.g., F1 score) for assessing hydrogen bond predictions. While CASP assessors commonly employ the harmonic mean (F1 score), the RNA-Puzzles contest has predominantly utilized the geometric mean (INF score) for evaluating RNA-related predictions. A key distinction between the evaluation methods in CASP and RNA-Puzzles lies in the granularity of interaction assessment. In CASP, individual hydrogen bonds are explicitly evaluated when calculating the F1 score. In contrast, RNA-Puzzles focuses on broader interaction assessments rather than individual hydrogen bonds. For instance, if two nucleotides in the reference structure are connected by three hydrogen bonds, but the predicted model shows the same nucleotides forming only two hydrogen bonds, the interaction is still considered a true positive. This approach disregards discrepancies in the exact number of hydrogen bonds, focusing instead on the presence of the interaction itself rather than its precise details. Such a solution seems more suitable for predictions that have not yet reached exceptional accuracy. In response to the Reviewer’s comment, we have implemented the F1 score in our scripts to enable direct comparison with I-INF. In both I-INF and F1 measures, an interaction is counted as a true positive regardless of the number of hydrogen bonds in the predicted model. Consequently, we updated Figure 1 (depicting the workflow) and revised the description of our program for molecular complex evaluation to reflect this addition. We also updated the manuscript title to emphasize the inclusion of multiple evaluation methods and our commitment to presenting a balanced and comprehensive analysis. Finally, it is worth noting that when evaluating multiple predictions, our program ranks them based on the value of the evaluation function. We designated I-INF as the primary arbiter, as substituting it with F1 would not affect the final ranking. {Comment 2:} TM-score an I-INF does NOT measure the same aspect of complex assembly. I-INF only evaluate the correctness of interface, while TM-score evaluates the global topology. There should be some theoretical justification on why TM-score has a high correlation with I-INF. {Response:} We appreciate the comment of the Reviewer on the correlation between TM-score and I-INF. In our opinion, the justification for the observed high correlation between these two measures is closely tied to the characteristics of the validation dataset. In general, the tertiary structures of the models closely resemble the reference structures, with the primary differences occurring at the interface regions, which is the focus of our evaluation. The validation set was specifically designed to assess the quality of methods evaluating intermolecular interfaces. Since I-INF is focused on assessing the accurracy of the interfaces, while TM-score evaluates the global topology, the significant overlap in terms of structural correctness at the interface region likely accounts for the high correlation between the two measures. This makes sense, as both metrics are sensitive to the accuracy of structural predictions, albeit with different scopes of evaluation. {Comment 3:} The title strongly suggest that I-INF works even for any biomacromolecular complexes including pure protein complexes. However, all evaluations in the result section are on protein-RNA complexes. There should be some application of I-INF on protein-protein complexes or explanation on why this is not applicable. {Response:} We thank the Reviewer for this observation. First, as mentioned in our response to Comment 1, we have updated the manuscript title to remove the explicit reference to I-INF. This change ensures that the title no longer implies an exclusive focus on this measure. Second, we agree that I-INF is not inherently limited to RNA-protein complexes. The measure is designed to evaluate the interface accuracy in any type of macromolecular complex. To demonstrate this, we have now included additional examples that apply I-INF to DNA-DNA, RNA-RNA, and protein-protein assemblies. They are available in our Zenodo repository (DOI: 10.5281/zenodo.14697284). This addition underscores the versatility of the I-INF measure and further substantiates its broader applicability beyond RNA-related systems. {Comment 4:} A major challenge in complex assembly evaluation is symmetric. For example, suppose the input is a tetramer containing two identical copies of a protein and two identical copies of an RNA, where the two RNA chains interact with each other. In this case, deriving a correct chain mapping for optimal I-INF is not trivial. This work simply ignore this challenge by forcing the user to input consistent chain ID mapping. This makes the program less useful. {Response:} We thank the Reviewer for raising this important point regarding the challenge of symmetric complexes. We acknowledge that deriving a correct chain mapping for complex assemblies, especially in cases of identical components such as in the example of tetramers, can be non-trivial. To address this issue, we have implemented a mechanism similar to that used in DockQv2. Specifically, we introduced an algorithm that efficiently iterates over all possible combinations of chains that can occur between the model and the reference structure. For each model, we now select the highest I-INF value from all analyzed chain mappings. To achieve this, we construct a bipartite graph that includes two independent layers of vertices corresponding to chains in the model and the reference structure. An edge is created between two vertices if the corresponding chains have identical sequences. We analyze all possible maximum matchings in this graph using Uno's algorithm (1997), which enumerates perfect, maximum, and maximal matchings in bipartite graphs. For the implementation, we used open-source code, which we refined by limiting it to the essential functions needed for our analysis. The source implementation is available at https://github.com/Xunius/bipartite_matching. This approach enhances our tool's ability to handle complex assemblies with symmetric components, making it more versatile and applicable to a broader range of systems. Examples of RNA-RNA and protein-protein interactions are provided (in our Zenodo repository) to illustrate its application. {Comment 5:} There is no support for mmCIF format, which is particularly relevant for this work which is supposed to work with large complexes with $>$65 chains. {Response:} Thank you for your feedback on the support for the mmCIF format. We acknowledge that the lack of mmCIF format support is a limitation, especially for large complexes with more than 65 chains, as you mentioned. As noted in the manuscript, the current version of the I-INF tool operates on PDB files due to the limitations of the HBPLUS library. However, we have already planned to implement support for the mmCIF format in future updates to address this limitation and improve the tool's applicability for larger RNA-protein complexes. We appreciate your valuable suggestion, and we will continue to work toward improving the capabilities of the tool in future versions. Reviewer 2 This work studies the evaluation of 3D structural prediction for macromolecular complexes, which is an essential problem in understanding cellular functions. The authors propose a novel metric, I-INF (Intermolecular Interaction Network Fidelity), to quantitatively assess the intermolecular interactions within multichain complexes. This manuscript is very well written and the I-INF score is useful. And I have only one minor comment about it. When comparing I-INF with existing methods such as TM-score and DockQv2, it is recommended to add a figure to make the comparison more clear. {Response:} We thank the Reviewer for the positive feedback and helpful suggestions. In response, we have added two scatter plots (Figure 3) to the manuscript that visualize the correlations between TM-score, DockQv2, and I-INF. Additionally, we have included a violin plot in the Supplementary Information (S1\_Figure.pdf) to illustrate how the values of these measures are spread across the benchmark set. Each violin corresponds to one measure, highlighting its central tendency and variability. We believe these additions enhance the clarity of our evaluation and strengthen the presentation of our findings. Attachments Attachment Submitted filename: Response-to-reviewers.pdf https://doi.org/10.1371/journal.pone.0319917.r003
7 Feb 2025 Decision Letter - Yong Wang, Editor PONE-D-24-53421R1Assessing interface accuracy in macromolecular complexesPLOS ONE Dear Dr. Szachniuk, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== Thank you for your revised manuscript and your response to the reviewer’s comments. However, the reviewer has pointed out that while their concern regarding the correlation between TM-score and I-INF was addressed in the response letter, no corresponding modifications were made in the manuscript itself. You should incorporate a theoretical justification within the manuscript explaining why TM-score has a high correlation with I-INF. This addition should ensure that the manuscript provides sufficient context and rationale for the use of these metrics in evaluating complex assembly. Please revise the manuscript accordingly and highlight the changes in your response letter. ============================== Please submit your revised manuscript by Mar 24 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Yong Wang Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data 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 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—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: I previously commented that "TM-score an I-INF does NOT measure the same aspect of complex assembly. I-INF only evaluate the correctness of interface, while TM-score evaluates the global topology. There should be some theoretical justification on why TM-score has a high correlation with I-INF." This revision only answer my question in the response letter, but did not make any corresponding modification in the manuscript. ****** 7. 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 ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment 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. Registration is free. 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 PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0319917.r004
Revision 2
7 Feb 2025 Author Response We thank the Reviewer for the supplementary suggestion. We have answered it in the revised version of the manuscript, and below we provide detailed explanations: Reviewer's comment: I previously commented that 'TM-score and I-INF do NOT measure the same aspect of complex assembly. I-INF only evaluates the correctness of the interface, while TM-score evaluates the global topology. There should be some theoretical justification on why TM-score has a high correlation with I-INF.' This revision only answered my question in the response letter, but did not make any corresponding modification in the manuscript. Response: Indeed, in the previous version of the manuscript, we did not include the appropriate modification in response to this comment. We have now addressed this. In the "Results and Discussion" section, we have inserted the following text: “Although TM-score evaluates the global topology of the model and I-INF specifically assesses the accuracy of the intermolecular interface, we observed a high Pearson correlation (0.73) between these metrics. This suggests that, in our dataset, a correctly predicted global fold is largely a consequence of the proper spatial arrangement of the molecular components, resulting in accurately modeled interfaces. In other words, deviations in the overall fold are primarily associated with errors in the interface regions. Therefore, high TM-score values frequently coincide with high I-INF values, highlighting our models' interdependence between global structural accuracy and interface correctness.” We hope that this addition provides the necessary theoretical justification for the observed high correlation between TM-score and I-INF. Attachments Attachment Submitted filename: response-to-referee.pdf https://doi.org/10.1371/journal.pone.0319917.r005
11 Feb 2025 Decision Letter - Yong Wang, Editor Assessing interface accuracy in macromolecular complexes PONE-D-24-53421R2 Dear Dr. Szachniuk, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Yong Wang Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0319917.r006
Formally Accepted
Acceptance Letter - Yong Wang, Editor PONE-D-24-53421R2 PLOS ONE Dear Dr. Szachniuk, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Yong Wang Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0319917.r007

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