Computational analysis of the deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in TYR gene impacting human tyrosinase protein and the protein stability

Wei Fan; Heng Li Ji; Mohibullah Kakar; Shabbir Ahmed; Hussah M. Alobaid; Yasmeen Shakir

doi:10.1371/journal.pone.0308927

Peer Review History

Original SubmissionAugust 5, 2023
18 Aug 2023 Decision Letter - Nihad A.M Al-Rashedi, Editor PONE-D-23-24946Computational analysis of damaging non-synonymous single nucleotide polymorphisms (nsSNPs) on human tyrosinase proteinPLOS ONE Dear Dr. Ahmed, 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. Please submit your revised manuscript by Oct 02 2023 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. 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To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ Additional Editor Comments: -The corresponding author doesn't match in the manuscript.docx copy with a manuscript draft form, it caused confusion. -The whole manuscript needs native-language editing. -Some texts are not based on the reference. ex. Line no. 89–90: -Line no. 29–93: The authors stated ''to date'' although citing this number and information from a reference published in 2001. -Line no. 38: keywords was not covering all input keys. [Note: HTML markup is below. Please do not edit.] [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.0308927.r001
Revision 1
6 Sep 2023 Author Response Dear Editor in Chief PLOS ONE After greeting I'd like to extend my thanks and appreciation for your kind efforts. This is regarding my manuscript Ref. Submission ID PONE-D-23-24946, entitled "Computational analysis of damaging non-synonymous single nucleotide polymorphisms (nsSNPs) on human tyrosinase protein". I confirm that all corrections, suggestions and queries made by the editor were all given full consideration. All corrections were made in the manuscript file and marked as track change. Our response against each recommendations is mentioned below. Additional Editor Comments: -The corresponding author doesn't match in the manuscript.docx copy with a manuscript draft form, it caused confusion. Response: Corrected -The whole manuscript needs native-language editing. Response: We have revised the language of manuscript with help the help of expert colleague. -Some texts are not based on the reference. ex. Line no. 89–90: Response: Revised -Line no. 29–93: The authors stated ''to date'' although citing this number and information from a reference published in 2001. Response: Revised -Line no. 38: keywords was not covering all input keys. Response: Revised The authors of this manuscript are grateful to the subject expert and editorial members of the journal, for valuable suggestions to improve the quality of our manuscript. We hope this version is suitable for acceptance and publication. _________________________ Shabbir Ahmed Corresponding author shabbirch983@gmail.com Attachments Attachment Submitted filename: Response latter.docx https://doi.org/10.1371/journal.pone.0308927.r002
8 Jan 2024 Decision Letter - Nihad A.M Al-Rashedi, Editor PONE-D-23-24946R1Computational analysis of damaging non-synonymous single nucleotide polymorphisms (nsSNPs) on human tyrosinase proteinPLOS ONE Dear Dr. Ahmed, 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. Your manuscript, “Computational analysis of damaging non-synonymous single nucleotide polymorphisms (nsSNPs) on human tyrosinase protein” [PONE-D-23-24946R1], has been assessed by our reviewers. Although it is of interest, we are unable to consider it for publication in its current form. The reviewers have raised a number of points that we believe would improve the manuscript and may allow a revised version to be published in PLOS ONE. Please submit your revised manuscript by Feb 22 2024 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, Nihad A.M Al-Rashedi Academic Editor PLOS ONE [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: All comments have been addressed Reviewer #2: (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: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: N/A ****** 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 Reviewer #2: No ****** 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 Reviewer #2: 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: Dear Editor, The manuscript, entitled "Computational analysis of damaging non-synonymous single nucleotide polymorphisms (nsSNPs) on human tyrosinase protein" is well written and all the sections of the manuscript are presented well and the work done by the authors is new and has scientific significance so this work can be considered for publication after checking these minor points: 1- Although it is extremely logical that interactions between the tyrosinase enzyme and compounds known as FDA-approved drugs as inhibitors have been made, I recommend examining the properties of two of the compounds that are claimed to be superior to the drugs determined by the FDA in the literature. 2- Newly synthesized tyrosinase inhibitors should be included in the "INTRODUCTION" section. Reviewer #2: Review Report Computational analysis of damaging non-synonymous single nucleotide polymorphisms (nsSNPs) on human tyrosinase protein The above manuscript is interesting in describing the structural and functional consequences of disease-associated non-synonymous single nucleotide polymorphisms (nsSNPs) in the TYR gene, which encodes tyrosinase. The study highlights the nsSNPs, notably K142M, I151N, M179R, S184L, L189P, and C321R, as particularly deleterious variants, which in general impact the structural integrity and functional behavior of human tyrosinase. The target is of importance; however, as a computational biologist, I am not confident about the outcomes of this study due to a limited and primary-level methodology. Following are some suggestions that need to be addressed before the final decision on the manuscript: 1. The title is very classical; preferably, it should be reworded. Specifically, the main components of the title should be rephrased with some smart, appealing words. 2. Abstract: The abstract is very plain and incomplete, lacking key content areas, and the research purpose was not properly addressed. The relevance or importance of the research work and the main outcomes were not discussed adequately. See lines 31–35; these lines seem to be an incorrect piece of information. It should be explained in detail regarding the methodological scope. What is the purpose of mentioning lines 37–38? Please explain. Please justify how this study advances the readers’ understanding of the molecular repercussions of the target’s gene and its variants. 3. Keywords: The keywords were not appropriate. Please recheck all selected words. 4. Introduction: This section looks like a mismatch of information. The introduction needs a thorough revision, especially in terms of describing the background of the gene or protein target selected, its clinical role, and its recent epidemiological impact on society. I absolutely missed thorough literature that represents a sound background of information from the present work. I would suggest here that authors should make this section a more comprehensive and updated flow of information that makes readers understand the importance of selected genes and why authors used them for this in silico genomic study. The study rational was missing from this section. Why are authors emphasizing that the main aim of this study is to see the significant role of non-synonymous genetic variations and their impact on the tyrosinase protein`s structure and function.? Specifically, the last paragraph was quite confusing and lacked clarity. The abstract isn’t organized and looks more like a mishmash of information. 5. Methodology: The very first sentence starts with “to date." I think it is better to mention the search timeline period. This section was absolutely incomplete. It is quite better if authors segregate the prediction methodologies separately in sub-headings. More importantly, this sub-division will help authors mention gene- or protein-based, sequence- or structure-based assessment methodologies. I found some repetition of details in this section. Although this is an optional suggestion, authors should add a flow chart with a better and more appealing way of presenting it. Please check the following manuscripts for a better reference. 6. DOI: 10.1021/acsomega.2c04871 7. DOI: 10.1021/acsptsci.2c00212 8. DOI: 10.1021/acs.jcim.0c00488 9. Results: I don’t accept the results in their present form. The results should be divided and subdivided according to the work scope. These aren’t acceptable in the present form. The graphical representations in the manuscript are of extremely low quality, and the authors are advised to use some smart tools to render high-quality, eye-catching plots of their data. 10. Discussion: It would be better to revise this section. Don’t provide too many details about the tools and methods used in the manuscript; focus more on whether your results are consistent and contribute to your overall findings in relation to previous studies and, finally, your future prospects. 11. Citations are missing in some cases. 12. Add a proper conclusion section to help readers retain the purpose of the article. Minor comments: 1. Cover letter: Please check the name and details of the corresponding author mentioned in the reply to the review letter. It should be the same as listed in the authors’ name list of this paper. 2. Kindly add some missing references. 3. Please refer to the above-recommended manuscripts for guidance on writing, figures, and work methodology. Good luck! ****** 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 Reviewer #2: 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. Attachments Attachment Submitted filename: Plos One Review Report.docx https://doi.org/10.1371/journal.pone.0308927.r003
Revision 2
14 Feb 2024 Author Response Dear Editor in Chief PLOS ONE After greeting I'd like to extend my thanks and appreciation for your kind efforts. This is regarding my manuscript Ref. Submission ID PONE-D-23-24946R1, entitled "Computational analysis of damaging non-synonymous single nucleotide polymorphisms (nsSNPs) on human tyrosinase protein". I confirm that all corrections, suggestions and queries made by the subject expert and all were given full consideration. All corrections were made in the manuscript file and marked as track change. Our response against each recommendations is mentioned below. Reviewer #1: The manuscript, entitled "Computational analysis of damaging non-synonymous single nucleotide polymorphisms (nsSNPs) on human tyrosinase protein" is well written and all the sections of the manuscript are presented well and the work done by the authors is new and has scientific significance so this work can be considered for publication after checking these minor points: Author Response: Thanks for appreciation, we have revise the all points raised by the subject expert Suggestion 1- Although it is extremely logical that interactions between the tyrosinase enzyme and compounds known as FDA-approved drugs as inhibitors have been made, I recommend examining the properties of two of the compounds that are claimed to be superior to the drugs determined by the FDA in the literature. Author Response: They have been added in the introduction as suggested. Moreover, a parallel study, we also docked literature-based effective tyrosinase inhibitor compounds and FDA-approved drugs with tyrosinase native and mutant models to see the binding affinity (Eb) and estimated equilibrium dissociation constant values (Kd). Therefore, we add the literature based information in introduction section that cover your query. Suggestion 2- Newly synthesized tyrosinase inhibitors should be included in the "INTRODUCTION" section. Author Response: Newly synthesized tyrosinase inhibitors have been added in the introduction as suggested as per recommendation. Reviewer #2: Suggestion 1- The above manuscript is interesting in describing the structural and functional consequences of disease-associated non-synonymous single nucleotide polymorphisms (nsSNPs) in the TYR gene, which encodes tyrosinase. The study highlights the nsSNPs, notably K142M, I151N, M179R, S184L, L189P, and C321R, as particularly deleterious variants, which in general impact the structural integrity and functional behavior of human tyrosinase. The target is of importance; however, as a computational biologist, I am not confident about the outcomes of this study due to a limited and primary-level methodology. Following are some suggestions that need to be addressed before the final decision on the manuscript: Author Response: Thanks for your suggestion to improve the quality of our research. We have incorporate all suggestion and recommendation in revised paper. Suggestion 2- The title is very classical; preferably, it should be reworded. Specifically, the main components of the title should be rephrased with some smart, appealing words. Author Response: Title has been reworded as suggested. Suggestion 3- Abstract: The abstract is very plain and incomplete, lacking key content areas, and the research purpose was not properly addressed. The relevance or importance of the research work and the main outcomes were not discussed adequately. See lines 31–35; these lines seem to be an incorrect piece of information. It should be explained in detail regarding the methodological scope. What is the purpose of mentioning lines 37–38? Please explain. Please justify how this study advances the readers’ understanding of the molecular repercussions of the target’s gene and its variants. Author Response: Thanks for suggestion. The abstract has been revised as suggested. Suggestion 4- Keywords: The keywords were not appropriate. Please recheck all selected words. Author Response: The new keywords were added according to the paper scope Suggestion 5- Introduction: This section looks like a mismatch of information. The introduction needs a thorough revision, especially in terms of describing the background of the gene or protein target selected, its clinical role, and its recent epidemiological impact on society. I absolutely missed thorough literature that represents a sound background of information from the present work. I would suggest here that authors should make this section a more comprehensive and updated flow of information that makes readers understand the importance of selected genes and why authors used them for this in silico genomic study. The study rational was missing from this section. Why are authors emphasizing that the main aim of this study is to see the significant role of non-synonymous genetic variations and their impact on the tyrosinase protein`s structure and function.? Specifically, the last paragraph was quite confusing and lacked clarity. The abstract isn’t organized and looks more like a mishmash of information. Author Response: Thanks for suggestion to improve the quality of my paper. We have extensively revised the introduction and follow the reviewer suggestion. Suggestion 6- Methodology: The very first sentence starts with “to date." I think it is better to mention the search timeline period. This section was absolutely incomplete. It is quite better if authors segregate the prediction methodologies separately in sub-headings. More importantly, this sub-division will help authors mention gene- or protein-based, sequence- or structure-based assessment methodologies. I found some repetition of details in this section. Although this is an optional suggestion, authors should add a flow chart with a better and more appealing way of presenting it. Please check the following manuscripts for a better reference. DOI: 10.1021/acsomega.2c04871 DOI: 10.1021/acsptsci.2c00212 DOI: 10.1021/acs.jcim.0c00488 Author Response: Methodology has been revised and improved following the suggestion of reviewer. Moreover, we have followed the above mentioned paper to revise the methodology section. Suggestion 7- Results: I don’t accept the results in their present form. The results should be divided and subdivided according to the work scope. These aren’t acceptable in the present form. The graphical representations in the manuscript are of extremely low quality, and the authors are advised to use some smart tools to render high-quality, eye-catching plots of their data. Author Response: Results were also revised as suggested by the reviewer. Furthermore, the results were presented in subsections as suggested. Additionally, we have improve the graphical representation of figures as suggested. Suggestion 8- Discussion: It would be better to revise this section. Don’t provide too many details about the tools and methods used in the manuscript; focus more on whether your results are consistent and contribute to your overall findings in relation to previous studies and, finally, your future prospects. Author Response: The discussion part was revised accordingly. Suggestion 9- Citations are missing in some cases. Author Response: The relevant citations were added in revised paper Suggestion 10- Add a proper conclusion section to help readers retain the purpose of the article. Author Response: A separate conclusion section was added in revise paper Minor comments: 1. Cover letter: Please check the name and details of the corresponding author mentioned in the reply to the review letter. It should be the same as listed in the authors’ name list of this paper. Done as per suggestion 2. Kindly add some missing references. Done as per suggestion 3. Please refer to the above-recommended manuscripts for guidance on writing, figures, and work methodology. Done as per suggestion The authors of this manuscript are grateful to the subject expert and editorial members of the journal, for valuable suggestions to improve the quality of our manuscript. We hope this version is suitable for acceptance and publication. _________________________ Shabbir Ahmed Corresponding author shabbirch983@gmail.com Attachments Attachment Submitted filename: Response latter.docx https://doi.org/10.1371/journal.pone.0308927.r004
17 Jul 2024 Decision Letter - Nihad A.M Al-Rashedi, Editor PONE-D-23-24946R2Computational analysis of the deleterious Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) in TYR gene impacting human Tyrosinase protein and the protein stabilityPLOS ONE Dear Dr. Ahmed, 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. Please submit your revised manuscript by Aug 31 2024 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, Nihad A.M Al-Rashedi 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: All comments have been addressed Reviewer #3: (No Response) Reviewer #4: All comments have been addressed ******** 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: Yes Reviewer #3: No Reviewer #4: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #3: N/A Reviewer #4: N/A ****** 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 Reviewer #3: Yes Reviewer #4: 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 Reviewer #3: No Reviewer #4: 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: Dear Editor, The authors have made the indicated corrections. However, the manuscript can be considered for publication after these minor points: Authors should cite some recent reports (2022-2023);new compounds for tyrosinase inhibition studies. (2023).ChemistrySelect,8(42),e202302936.https://doi.org/10.1002/slct.202302936 (2023). Journal of Biomolecular Structure and Dynamics, 41(15), 7128-7143. https://doi.org/10.1080/07391102.2022.2116600 (2022). Journal of Molecular Structure, 1257, 132641. https://doi.org/10.1016/j.molstruc.2022.132641 (2022). Chemistry & Biodiversity, 19(6), e202200140. Reviewer #3: There is scientific merit in the manuscript titled “Computational analysis of the deleterious Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) in TYR gene impacting human Tyrosinase protein and the protein stability”. However, the manuscript should be improved significantly before it can be published. Major points: 1. The rationale for the molecular docking studies is not established. It is also unclear how the docking results support the predictions of the pathogenicity of the SNPs. None of the studied FDA-approved drugs are present in the crystal structure (PDB ID: 7RK7) used for docking. Thus, there is no control for this docking analysis. 2. This is purely a computational study. Results should further be validated using replicated long molecular dynamics simulations. 3. Substantial language editing will be needed. There are many grammar errors. Reviewer #4: It is a well planned and presented study. All the queries raised by reviewers have been answered satisfactorily and manuscript revised accordingly. The manuscript can now be considered for publication. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). 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Revision 3
26 Jul 2024 Author Response Dear Editor in Chief PLOS ONE After greeting I'd like to extend my thanks and appreciation for your kind efforts. This is regarding my manuscript Ref. Submission ID PONE-D-23-24946R2, entitled " Computational analysis of the deleterious Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) in TYR gene impacting human tyrosinase protein and the protein stability". I confirm that all corrections, suggestions and queries made by the subject expert and all were given full consideration. All corrections were made in the manuscript file and marked as track change. Our response against each recommendations is mentioned below. 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: The authors have made the indicated corrections. However, the manuscript can be considered for publication after these minor points: Query 1: Authors should cite some recent reports (2022-2023);new compounds for tyrosinase inhibition studies. (2023).ChemistrySelect,8(42),e202302936.https://doi.org/10.1002/slct.202302936 (2023). Journal of Biomolecular Structure and Dynamics, 41(15), 7128-7143. https://doi.org/10.1080/07391102.2022.2116600 (2022). Journal of Molecular Structure, 1257, 132641. https://doi.org/10.1016/j.molstruc.2022.132641 (2022). Chemistry & Biodiversity, 19(6), e202200140. Response: Thanks for consideration of our paper. We have added the all suggested references and highlighted in red color Reviewer #3: There is scientific merit in the manuscript titled “Computational analysis of the deleterious Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) in TYR gene impacting human Tyrosinase protein and the protein stability”. However, the manuscript should be improved significantly before it can be published. Major points: Query 1: The rationale for the molecular docking studies is not established. It is also unclear how the docking results support the predictions of the pathogenicity of the SNPs. Response: Molecular docking allowed us to explore how FDA-approved drugs interact with both wild-type and mutant forms of Tyrosinase. This revealed potential therapeutic compounds that might mitigate the effects of pathogenic mutations. Our study identified specific interactions between proposed drugs and mutant Tyrosinase models, suggesting potential pathways for pharmaceutical intervention. Docking studies serve as a predictive tool to screen and rank potential drug candidates based on their binding affinities. This computational approach is cost-effective and time-efficient compared to experimental high-throughput screening methods. The docking scores and binding affinities provide quantitative measures of how mutations impact the protein's ability to interact with ligands. Mutations that significantly reduce binding affinity or alter binding modes can be indicative of a loss of function or destabilization of the protein, which are hallmarks of pathogenic variants. By visualizing the docking poses, we can identify structural changes in the protein that result from the mutations. These changes can disrupt the active site or other critical regions of the protein, leading to impaired function. For instance, our study showed that mutations like K142M and I151N led to altered binding interactions with FDA-approved drugs, highlighting their potential pathogenic impact. Query 2: None of the studied FDA-approved drugs are present in the crystal structure (PDB ID: 7RK7) used for docking. Thus, there is no control for this docking analysis. Addressing the Absence of FDA-Approved Drugs in the Crystal Structure (PDB ID: 7RK7) Response: The concern regarding the absence of FDA-approved drugs in the crystal structure used for docking is valid. Here are the steps we have taken to address this issue: Use of AlphaFold Models: Given the limitations of available crystal structures, we utilized AlphaFold-predicted models to obtain a more complete and accurate representation of the Tyrosinase protein. This approach allows us to explore the full binding potential of the protein, including regions not covered by the existing crystal structure. Comparative Analysis: We conducted docking studies on both wild-type and mutant models of Tyrosinase to compare the binding interactions. This comparative approach helps highlight the specific effects of the mutations and provides a control for our docking analysis Query 3: This is purely a computational study. Results should further be validated using replicated long molecular dynamics simulations. Response: We appreciate the reviewer's suggestion to validate our computational docking results using long molecular dynamics (MD) simulations. While we acknowledge the value of MD simulations in providing dynamic insights into protein-ligand interactions, it is important to note that this study's primary focus is on the initial identification and characterization of deleterious nsSNPs in the TYR gene and their potential impact on protein stability and drug binding. The findings from our docking studies provide valuable initial insights that can inform more detailed follow-up studies, including MD simulations and experimental validations. Conducting long MD simulations for multiple protein-ligand complexes would require substantial computational resources and time, which are beyond the current scope and budget of this study. Query 4: Substantial language editing will be needed. There are many grammar errors. Response: With the help of expert collogue, we have gone through the manuscript and made significant correction for typos and grammatical errors for the overall improvement of language. Reviewer #4: It is a well-planned and presented study. All the queries raised by reviewers have been answered satisfactorily and manuscript revised accordingly. The manuscript can now be considered for publication. Response: We appreciate the comments made the reviewer and its recommendation for acceptance of this manuscript. The authors of this manuscript are grateful to the subject expert and editorial members of the journal, for valuable suggestions to improve the quality of our manuscript. We hope this version is suitable for acceptance and publication. _________________________ Shabbir Ahmed Corresponding author shabbirch983@gmail.com Attachments Attachment Submitted filename: Response latter.docx https://doi.org/10.1371/journal.pone.0308927.r006
2 Aug 2024 Decision Letter - Nihad A.M Al-Rashedi, Editor Computational analysis of the deleterious Non-Synonymous Single Nucleotide Polymorphisms (nsSNPs) in TYR gene impacting human tyrosinase protein and the protein stability PONE-D-23-24946R3 Dear Dr. Ahmed, 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, Nihad A.M Al-Rashedi Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0308927.r007
Formally Accepted
5 Nov 2024 Acceptance Letter - Nihad A.M Al-Rashedi, Editor PONE-D-23-24946R3 PLOS ONE Dear Dr. Ahmed, 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. Nihad A.M Al-Rashedi Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0308927.r008

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