{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T11:01:49Z","timestamp":1767178909518,"version":"build-2238731810"},"update-to":[{"DOI":"10.12688\/f1000research.8853.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2016,9,14]],"date-time":"2016-09-14T00:00:00Z","timestamp":1473811200000}}],"reference-count":91,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2016,9,14]],"date-time":"2016-09-14T00:00:00Z","timestamp":1473811200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"\n The dramatic transformation of the Zika virus (ZIKV) from a relatively unknown virus to a pathogen generating global-wide panic has exposed the dearth of detailed knowledge about this virus. Decades of research in the related Dengue virus (DENV), finally culminating in a vaccine registered for use in endemic regions (CYD-TDV) in three countries, provides key insights in developing strategies for tackling ZIKV, which has caused global panic to microcephaly and Guillain-Barre Syndrome. Dengue virus (DENV), a member of the family\n Flaviviridae<\/ns4:italic>\n , the causal agent of the self-limiting Dengue fever and the potentially fatal hemorrhagic fever\/dengue shock syndrome, has been a scourge in tropical countries for many centuries. The recently solved structure of mature ZIKV (PDB ID:5IRE) has provided key insights into the structure of the envelope (E) and membrane (M) proteins, the primary target of neutralizing antibodies. The previously established MEPP methodology compares two conformations of the same protein and identifies residues with significant spatial and electrostatic perturbations. In the current work, MEPP analyzed the pre-and post-fusion DENV type 2 envelope (E) protein, and identified several known epitopes (His317, Tyr299, Glu26, Arg188, etc.) (MEPPitope). These residues are overwhelmingly conserved in ZIKV and all DENV serotypes, and also enumerates residue pairs that undergo significant polarity reversal. Characterization of \u03b1-helices in E-proteins show that \u03b11 is not conserved in the sequence space of ZIKV and DENV. Furthermore, perturbation of \u03b11 in the post-fusion DENV structure includes a known epitope Asp215, a residue absent in the pre-fusion \u03b11. A cationic \u03b2-sheet in the GAG-binding domain that is stereochemically equivalent in ZIKV and all DENV serotypes is also highlighted due to a residue pair (Arg286-Arg288) that has a significant electrostatic polarity reversal upon fusion. Finally, two highly conserved residues (Thr32 and Thr40), with little emphasis in existing literature, are found to have significant electrostatic perturbation. Thus, a combination of different computational methods enable the rapid and rational detection of critical residues as epitopes in the search for an elusive therapy or vaccine that neutralizes multiple members of the\n Flaviviridae<\/ns4:italic>\n family. These secondary structures are conserved in the related Dengue virus (DENV), and possibly rationalize isolation techniques particle adsorption on magnetic beads coated with anionic polymers and anionic antiviral agents (viprolaxikine) for DENV. These amphipathic \u03b1-helices could enable design of molecules for inhibiting \u03b1-helix mediated protein-protein interactions. Finally, comparison of these secondary structures in proteins from related families illuminate subtle changes in the proteins that might render them ineffective to previously successful drugs and vaccines, which are difficult to identify by a simple sequence or structural alignment. Finally, conflicting results about residues that are involved in neutralizing a DENV-E protein by the potent antibody 5J7 (PDB ID:3J6U) are reported.\n <\/ns4:p>","DOI":"10.12688\/f1000research.8853.2","type":"journal-article","created":{"date-parts":[[2016,9,14]],"date-time":"2016-09-14T06:50:09Z","timestamp":1473835809000},"page":"1150","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Computational analysis of perturbations in the post-fusion Dengue virus envelope protein highlights known epitopes and conserved residues in the Zika virus"],"prefix":"10.12688","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0455-0723","authenticated-orcid":false,"given":"Sandeep","family":"Chakraborty","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2016,9,14]]},"reference":[{"key":"ref-1","doi-asserted-by":"crossref","first-page":"73-83","DOI":"10.1128\/JVI.72.1.73-83.1998","article-title":"Phylogeny of the genus Flavivirus.","volume":"72","author":"G Kuno","year":"1998","journal-title":"J Virol."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"13-22","DOI":"10.1038\/nrmicro1067","article-title":"A structural perspective of the flavivirus life cycle.","volume":"3","author":"S Mukhopadhyay","year":"2005","journal-title":"Nat Rev Microbiol."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"7100-7111","DOI":"10.1016\/j.vaccine.2015.09.108","article-title":"Development of the Sanofi Pasteur tetravalent 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Chakraborty","year":"2016","journal-title":"F1000Research."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/5-1150\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/5-1150\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/5-1150\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T23:12:39Z","timestamp":1692486759000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/5-1150\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,14]]},"references-count":91,"URL":"https:\/\/doi.org\/10.12688\/f1000research.8853.2","relation":{},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,9,14]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/5-1150\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.9528.r14191, Shamala\u00a0Devi Sekaran, Keivan Zandi, Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia, 15 Jun 2016, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/5-1150\/v1#referee-response-14191","order":0,"name":"referee-response-14191","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"Sandeep Chakraborty<\/b>; Posted: 08 Sep 2016<\/i>; Dear Dr Sekaran and Dr Zandi, I would like to thank you for taking the time to review this paper, and providing constructive criticism on the overall manuscript. I have revised the manuscript based on the comment of all three reviewers. Please find my responses below.     The title needs to be shortened and revised as the should reflect the nature of the work which is all computational<\/b>     >> Done.              Some other minor comments             a. vaccine is only registered to date in 3 countries and not used by endemic regions as stated in line 4 of the abstract - please rewrite this.<\/b>             >> Done              b. The last sentence has to be revised as I am not sure this addresses targets for drugs<\/b>             >> Revised. I have made the changes in the main manuscript too.              c. The last paragraph of introduction - was quantitative analysis of Den-2 E done with MEPP?<\/b>             >> Yes.             d. Please check citation of APBS (version 1.4) which is given as Ref 52<\/b>             >> Ref 52 was intended to direct the reader to the parameters used. I have cited APBS before this reference to remove the confusion.              e. In the analysis of secondary structures - first sentence needs to revise as this was only done for the E protein and not all proteins<\/b>             >> Fixed. I would like to thank you once again for the positive comments. best wishes, Sandeep","URL":"https:\/\/f1000research.com\/articles\/5-1150\/v2#referee-comment-2177","order":1,"name":"referee-comment-2177","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.9528.r15004, Raju Nagarajan, Vanderbilt Vaccine Center, Vanderbilt Medical Center, Nashville, TN, USA, 28 Jul 2016, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/5-1150\/v1#referee-response-15004","order":2,"name":"referee-response-15004","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"Sandeep Chakraborty<\/b>; Posted: 08 Sep 2016<\/i>; Dear Dr Nagarajan, I would like to thank you for taking the time to review this paper, and providing constructive criticism on the overall manuscript. I have revised the manuscript based on the comment of all three reviewers. Please find my responses below. The author performed an essential structural analysis of ZIKV and DENV envelope proteins and reported the identification of unreported epitope residues with conservation details. The quality of writing and analysis is acceptable with some minor corrections.     The text is not much visible in Figure 6 and has to be revised.<\/b>     >> This figure is high resolution, and text is visible clearly. I will request the typesetting to increase the size of this figure in the pdf.     In the caption of figure 5, it should be "192-195" instead of "192-95".<\/b>     >> Done.     Title should be shortened.<\/b>     >> Done.     The first sentence in the "Analysis of secondary structures" has to be revised to ensure that the analysis only performed for envelope proteins.<\/b>     >> Done. I would like to thank you once again for the positive comments. best wishes, Sandeep","URL":"https:\/\/f1000research.com\/articles\/5-1150\/v2#referee-comment-2176","order":3,"name":"referee-comment-2176","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.9528.r15317, Yi Shi, Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, \u00a0Chinese Academy of Sciences, Beijing, China, 29 Jul 2016, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/5-1150\/v1#referee-response-15317","order":4,"name":"referee-response-15317","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"Sandeep Chakraborty<\/b>; Posted: 08 Sep 2016<\/i>; Dear Dr Shi, I would like to thank you for taking the time to review this paper, and providing constructive criticism on the overall manuscript. I have revised the manuscript based on the comment of all three reviewers. Please find my responses below. In the manuscript entitled " MEPPitope: spatial, electrostatic and secondary structure perturbations in the post-fusion Dengue virus envelope protein highlights known epitopes and conserved residues in the Zika virus", Sandeep Chakraborty analyzed the pre- and post-fusion DENV type 2 envelope (E) protein, and identified several known epitopes, which are conserved in ZIKV and all DENV serotypes. Perturbations of spatial and electrostatic or secondary structure identified by a combination of different computational methods help to detect critical residues that can be made target of therapies. Overall, the paper provides interesting data. The paper could be improved by addressing the following points:       The title is too long and needs to be shortened.<\/b>     >> Done.            There are some new antibodies against ZIKV or DENV reported recently, the paper would benefit by adding new information.   <\/b> >> Ref 79 and 88 have been added.      <\/b>     \u03b1 5 and 6 are not labeled in Figure 1.<\/b>     >> Done.      In the section of \u201cconflicting data in comparison to previous studies\u201d line 9, the statement \u201c\u2026 from another E-protein of the same subunit\u201d is inaccurate as subunit refers to a single polypeptide chain.<\/b>     >> The word "subunit" has been replaced with "complex". I would like to thank you once again for the positive comments. best wishes, Sandeep","URL":"https:\/\/f1000research.com\/articles\/5-1150\/v2#referee-comment-2175","order":5,"name":"referee-comment-2175","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author(s) declared that no grants were involved in supporting this work","order":6,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Data associated with the article are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).","order":0,"name":"copyright-info","label":"Copyright"}]}}