{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:35:47Z","timestamp":1790804147262,"version":"4.1.0"},"reference-count":111,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T00:00:00Z","timestamp":1638921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Spike glycoprotein (Sgp) is liable for binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the host receptors. Since Sgp is the main target for vaccine and drug designing, elucidating its mutation pattern could help in this regard. This study is aimed at investigating the correspondence of specific residues to the Sgp<jats:sub>SARS-CoV-2<\/jats:sub> functionality by explorative interpretation of sequence alignments. Centrality analysis of the Sgp dissects the importance of these residues in the interaction network of the RBD-ACE2 (receptor-binding domain) complex and furin cleavage site. Correspondence of RBD to threonine500 and asparagine501 and furin cleavage site to glutamine675, glutamine677, threonine678, and alanine684 was observed; all residues are exactly located at the interaction interfaces. The harmonious location of residues dictates the RBD binding property and the flexibility, hydrophobicity, and accessibility of the furin cleavage site. These species-specific residues can be assumed as real targets of evolution, while other substitutions tend to support them. Moreover, all these residues are parts of experimentally identified epitopes. Therefore, their substitution may affect vaccine efficacy. Higher rate of RBD maintenance than furin cleavage site was predicted. The accumulation of substitutions reinforces the probability of the multi-host circulation of the virus and emphasizes the enduring evolutionary events.<\/jats:p>","DOI":"10.1038\/s41598-021-01655-y","type":"journal-article","created":{"date-parts":[[2021,12,8]],"date-time":"2021-12-08T11:03:07Z","timestamp":1638961387000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Hotspots for mutations in the SARS-CoV-2 spike glycoprotein: a correspondence analysis"],"prefix":"10.1038","volume":"11","author":[{"given":"Mohammad Reza","family":"Rahbar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abolfazl","family":"Jahangiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeed","family":"Khalili","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahboubeh","family":"Zarei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamran","family":"Mehrabani-Zeinabad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahman","family":"Khalesi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navid","family":"Pourzardosht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anahita","family":"Hessami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Navid","family":"Nezafat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saman","family":"Sadraei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manica","family":"Negahdaripour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,12,8]]},"reference":[{"key":"1655_CR1","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1080\/21645515.2020.1833577","volume":"17","author":"P Mosaddeghi","year":"2021","unstructured":"Mosaddeghi, P., Shahabinezhad, F., Dorvash, M., Goodarzi, M. & Negahdaripour, M. Harnessing the non-specific immunogenic effects of available vaccines to combat COVID-19. Hum. Vaccin. Immunother. 17, 1650\u20131661 (2021).","journal-title":"Hum. Vaccin. Immunother."},{"key":"1655_CR2","first-page":"235","volume":"46","author":"M Negahdaripour","year":"2021","unstructured":"Negahdaripour, M. Post-COVID-19 hyperglycemia: A concern in selection of therapeutic regimens. Iran. J. Med. Sci. 46, 235\u2013236 (2021).","journal-title":"Iran. J. Med. Sci."},{"key":"1655_CR3","doi-asserted-by":"crossref","unstructured":"Greenstone, M. & Nigam, V. Does social distancing matter? University of Chicago, Becker Friedman Institute for Economics Working Paper (2020).","DOI":"10.2139\/ssrn.3561244"},{"key":"1655_CR4","first-page":"1","volume":"6","author":"Y Zhou","year":"2020","unstructured":"Zhou, Y. et al. Network-based drug repurposing for novel coronavirus 2019-nCoV\/SARS-CoV-2. Cell discov. 6, 1\u201318 (2020).","journal-title":"Cell discov."},{"key":"1655_CR5","doi-asserted-by":"crossref","first-page":"110425","DOI":"10.1016\/j.jtbi.2020.110425","volume":"505","author":"Z Payandeh","year":"2020","unstructured":"Payandeh, Z. et al. Design of an engineered ACE2 as a novel therapeutics against COVID-19. J. Theor. Biol. 505, 110425 (2020).","journal-title":"J. Theor. Biol."},{"key":"1655_CR6","first-page":"m4975","volume":"371","author":"A Bagheri","year":"2020","unstructured":"Bagheri, A. et al. Covid-19: Russia admits to understating deaths by more than two thirds. BMJ 371, m4975 (2020).","journal-title":"BMJ"},{"key":"1655_CR7","doi-asserted-by":"crossref","first-page":"684020","DOI":"10.3389\/fmed.2021.684020","volume":"8","author":"VK Bhardwaj","year":"2021","unstructured":"Bhardwaj, V. K. et al. Bioactive molecules of Tea as potential inhibitors for RNA-dependent RNA polymerase of SARS-CoV-2. Front. Med. 8, 684020 (2021).","journal-title":"Front. Med."},{"key":"1655_CR8","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1080\/10408363.2020.1783198","volume":"57","author":"M Ciotti","year":"2020","unstructured":"Ciotti, M. et al. The COVID-19 pandemic. Crit. Rev. Clin. Lab. Sci. 57, 365\u2013388 (2020).","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"1655_CR9","doi-asserted-by":"crossref","first-page":"282","DOI":"10.3389\/fmolb.2021.669431","volume":"8","author":"ZS Hashemi","year":"2021","unstructured":"Hashemi, Z. S. et al. In silico approaches for the design and optimization of interfering peptides against protein\u2013protein interactions. Front. Mol. Biosci. 8, 282 (2021).","journal-title":"Front. Mol. Biosci."},{"key":"1655_CR10","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1016\/j.cell.2020.07.012","volume":"182","author":"Q Li","year":"2020","unstructured":"Li, Q. et al. The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity. Cell 182, 1284-1294.e1289 (2020).","journal-title":"Cell"},{"key":"1655_CR11","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.3390\/v4061011","volume":"4","author":"S Belouzard","year":"2012","unstructured":"Belouzard, S., Millet, J. K., Licitra, B. N. & Whittaker, G. R. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses 4, 1011\u20131033 (2012).","journal-title":"Viruses"},{"key":"1655_CR12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11756-021-00866-y","volume":"76","author":"B Vakili","year":"2021","unstructured":"Vakili, B., Bagheri, A. & Negahdaripour, M. Deep survey for designing a vaccine against SARS-CoV-2 and its new mutations. Biologia 76, 1\u201312 (2021).","journal-title":"Biologia"},{"key":"1655_CR13","first-page":"157","volume-title":"Nidoviruses","author":"BJ Bosch","year":"2008","unstructured":"Bosch, B. J. & Rottier, P. J. Nidoviruses 157\u2013178 (American Society of Microbiology, 2008)."},{"key":"1655_CR14","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.cell.2020.02.058","volume":"181","author":"AC Walls","year":"2020","unstructured":"Walls, A. C. et al. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 181, 281-292.e286. https:\/\/doi.org\/10.1016\/j.cell.2020.02.058 (2020).","journal-title":"Cell"},{"key":"1655_CR15","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.virusres.2014.11.021","volume":"202","author":"JK Millet","year":"2015","unstructured":"Millet, J. K. & Whittaker, G. R. Host cell proteases: Critical determinants of coronavirus tropism and pathogenesis. Virus Res. 202, 120\u2013134 (2015).","journal-title":"Virus Res."},{"key":"1655_CR16","doi-asserted-by":"crossref","first-page":"C8","DOI":"10.1016\/j.vaccine.2008.04.011","volume":"26","author":"MF Boni","year":"2008","unstructured":"Boni, M. F. Vaccination and antigenic drift in influenza. Vaccine 26, C8\u2013C14 (2008).","journal-title":"Vaccine"},{"key":"1655_CR17","doi-asserted-by":"crossref","unstructured":"Cianci, R., Newton, E. E. & Pagliari, D. Efforts to Improve the Seasonal Influenza Vaccine (Multidisciplinary Digital Publishing Institute, 2020).","DOI":"10.3390\/vaccines8040645"},{"key":"1655_CR18","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.3000003","volume":"16","author":"S Duffy","year":"2018","unstructured":"Duffy, S. Why are RNA virus mutation rates so damn high?. PLoS Biol. 16, e3000003 (2018).","journal-title":"PLoS Biol."},{"key":"1655_CR19","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1093\/nsr\/nwaa036","volume":"7","author":"X Tang","year":"2020","unstructured":"Tang, X. et al. On the origin and continuing evolution of SARS-CoV-2. Natl. Sci. Rev. 7, 1012\u20131023 (2020).","journal-title":"Natl. Sci. Rev."},{"key":"1655_CR20","doi-asserted-by":"crossref","first-page":"9241","DOI":"10.1073\/pnas.2004999117","volume":"117","author":"P Forster","year":"2020","unstructured":"Forster, P., Forster, L., Renfrew, C. & Forster, M. Phylogenetic network analysis of SARS-CoV-2 genomes. Proc. Natl. Acad. Sci. 117, 9241\u20139243 (2020).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"1655_CR21","doi-asserted-by":"crossref","first-page":"104260","DOI":"10.1016\/j.meegid.2020.104260","volume":"81","author":"T Phan","year":"2020","unstructured":"Phan, T. Genetic diversity and evolution of SARS-CoV-2. Infect. Genet. Evol. 81, 104260 (2020).","journal-title":"Infect. Genet. Evol."},{"key":"1655_CR22","doi-asserted-by":"crossref","first-page":"100673","DOI":"10.1016\/j.nmni.2020.100673","volume":"35","author":"AA Dawood","year":"2020","unstructured":"Dawood, A. A. Mutated COVID-19, may foretells mankind in a great risk in the future. New Microbes New Infect. 35, 100673 (2020).","journal-title":"New Microbes New Infect."},{"key":"1655_CR23","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.cell.2020.06.043","volume":"182","author":"B Korber","year":"2020","unstructured":"Korber, B. et al. Tracking changes in SARS-CoV-2 Spike: Evidence that D614G increases infectivity of the COVID-19 virus. Cell 182, 812\u2013827 (2020).","journal-title":"Cell"},{"key":"1655_CR24","doi-asserted-by":"crossref","first-page":"eabe0948","DOI":"10.1126\/scitranslmed.abe0948","volume":"12","author":"BF Haynes","year":"2020","unstructured":"Haynes, B. F. et al. Prospects for a safe COVID-19 vaccine. Sci. Transl. Med. 12, eabe0948 (2020).","journal-title":"Sci. Transl. Med."},{"key":"1655_CR25","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1016\/S0264-410X(00)00468-0","volume":"19","author":"P-L Tan","year":"2001","unstructured":"Tan, P.-L., Jacobson, R. M., Poland, G. A., Jacobsen, S. J. & Pankratz, V. S. Twin studies of immunogenicity\u2014Determining the genetic contribution to vaccine failure. Vaccine 19, 2434\u20132439 (2001).","journal-title":"Vaccine"},{"key":"1655_CR26","doi-asserted-by":"crossref","first-page":"vew014","DOI":"10.1093\/ve\/vew014","volume":"2","author":"KK Irwin","year":"2016","unstructured":"Irwin, K. K., Renzette, N., Kowalik, T. F. & Jensen, J. D. Antiviral drug resistance as an adaptive process. Virus Evol. 2, vew014 (2016).","journal-title":"Virus Evol."},{"key":"1655_CR27","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1001\/jama.2021.2088","volume":"325","author":"JR Mascola","year":"2021","unstructured":"Mascola, J. R., Graham, B. S. & Fauci, A. S. SARS-CoV-2 viral variants\u2014Tackling a moving target. JAMA 325, 1261\u20131262 (2021).","journal-title":"JAMA"},{"key":"1655_CR28","first-page":"815","volume":"372","author":"NR Faria","year":"2021","unstructured":"Faria, N. R. et al. Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: Preliminary findings. Virological 372, 815\u2013821 (2021).","journal-title":"Virological"},{"key":"1655_CR29","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.1016\/j.cell.2021.03.052","volume":"184","author":"NL Washington","year":"2021","unstructured":"Washington, N. L. et al. Emergence and rapid transmission of SARS-CoV-2 B. 1.1. 7 in the United States. Cell 184, 2587\u20132594 (2021).","journal-title":"Cell"},{"key":"1655_CR30","first-page":"1530","volume":"37","author":"E Volz","year":"2021","unstructured":"Volz, E. et al. Transmission of SARS-CoV-2 Lineage B. 1.1. 7 in England: Insights from linking epidemiological and genetic data. medRxiv 37, 1530 (2021).","journal-title":"medRxiv"},{"key":"1655_CR31","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1002\/pro.2930","volume":"25","author":"RA Goldstein","year":"2016","unstructured":"Goldstein, R. A. & Pollock, D. D. The tangled bank of amino acids. Protein Sci. 25, 1354\u20131362 (2016).","journal-title":"Protein Sci."},{"key":"1655_CR32","doi-asserted-by":"crossref","first-page":"E1352","DOI":"10.1073\/pnas.1120084109","volume":"109","author":"DD Pollock","year":"2012","unstructured":"Pollock, D. D., Thiltgen, G. & Goldstein, R. A. Amino acid coevolution induces an evolutionary Stokes shift. Proc. Natl. Acad. Sci. 109, E1352\u2013E1359 (2012).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"1655_CR33","doi-asserted-by":"crossref","first-page":"E1450","DOI":"10.1073\/pnas.1401112111","volume":"111","author":"DD Pollock","year":"2014","unstructured":"Pollock, D. D. & Goldstein, R. A. Strong evidence for protein epistasis, weak evidence against it. Proc. Natl. Acad. Sci. 111, E1450\u2013E1450 (2014).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"1655_CR34","doi-asserted-by":"crossref","first-page":"e77","DOI":"10.1093\/nar\/gkw022","volume":"44","author":"RF Schwarz","year":"2016","unstructured":"Schwarz, R. F. et al. ALVIS: interactive non-aggregative visualization and explorative analysis of multiple sequence alignments. Nucleic Acids Res. 44, e77\u2013e77 (2016).","journal-title":"Nucleic Acids Res."},{"key":"1655_CR35","doi-asserted-by":"crossref","first-page":"5959","DOI":"10.1093\/nar\/gkp634","volume":"37","author":"R Schwarz","year":"2009","unstructured":"Schwarz, R. et al. Detecting species-site dependencies in large multiple sequence alignments. Nucleic Acids Res. 37, 5959\u20135968 (2009).","journal-title":"Nucleic Acids Res."},{"key":"1655_CR36","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1126\/science.1116480","volume":"309","author":"F Li","year":"2005","unstructured":"Li, F., Li, W., Farzan, M. & Harrison, S. C. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science 309, 1864\u20131868 (2005).","journal-title":"Science"},{"key":"1655_CR37","doi-asserted-by":"crossref","first-page":"23815","DOI":"10.1039\/D1RA03299B","volume":"11","author":"Z Sheybani","year":"2021","unstructured":"Sheybani, Z. et al. The interactions of folate with the enzyme furin: A computational study. RSC Adv. 11, 23815\u201323824 (2021).","journal-title":"RSC Adv."},{"key":"1655_CR38","first-page":"1","volume":"2","author":"S Tian","year":"2012","unstructured":"Tian, S., Huajun, W. & Wu, J. Computational prediction of furin cleavage sites by a hybrid method and understanding mechanism underlying diseases. Sci. Rep. 2, 1\u20137 (2012).","journal-title":"Sci. Rep."},{"key":"1655_CR39","doi-asserted-by":"crossref","first-page":"S2049","DOI":"10.4137\/BCI.S2049","volume":"2","author":"S Tian","year":"2009","unstructured":"Tian, S. A 20 residues motif delineates the furin cleavage site and its physical properties may influence viral fusion. Biochem. Insights 2, S2049 (2009).","journal-title":"Biochem. Insights"},{"key":"1655_CR40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12866-020-02060-7","volume":"21","author":"Y Zhang","year":"2021","unstructured":"Zhang, Y. et al. A newly identified linear epitope on non-RBD region of SARS-CoV-2 spike protein improves the serological detection rate of COVID-19 patients. BMC Microbiol. 21, 1\u201311 (2021).","journal-title":"BMC Microbiol."},{"key":"1655_CR41","doi-asserted-by":"publisher","unstructured":"Snyder, T. M., Gittelman, R. M., Klinger, M. et al. Magnitude and dynamics of the T-cell response to SARS-CoV-2 infection at both individual and population levels. Preprint. medRxiv. 2020.07.31.20165647. https:\/\/doi.org\/10.1101\/2020.07.31.20165647 (2020).","DOI":"10.1101\/2020.07.31.20165647"},{"key":"1655_CR42","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1126\/science.abd2321","volume":"369","author":"M Yuan","year":"2020","unstructured":"Yuan, M. et al. Structural basis of a shared antibody response to SARS-CoV-2. Science 369, 1119\u20131123 (2020).","journal-title":"Science"},{"key":"1655_CR43","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.cell.2020.09.035","volume":"183","author":"S Du","year":"2020","unstructured":"Du, S. et al. Structurally resolved SARS-CoV-2 antibody shows high efficacy in severely infected hamsters and provides a potent cocktail pairing strategy. Cell 183, 1013-1023.e1013 (2020).","journal-title":"Cell"},{"key":"1655_CR44","doi-asserted-by":"crossref","first-page":"3.5.1","DOI":"10.1002\/0471250953.bi0305s43","volume":"43","author":"WR Pearson","year":"2013","unstructured":"Pearson, W. R. Selecting the right similarity-scoring matrix. Curr. Protoc. Bioinform. 43, 3.5.1-3.5.9 (2013).","journal-title":"Curr. Protoc. Bioinform."},{"key":"1655_CR45","doi-asserted-by":"crossref","first-page":"11892","DOI":"10.1128\/JVI.79.18.11892-11900.2005","volume":"79","author":"B Kan","year":"2005","unstructured":"Kan, B. et al. Molecular evolution analysis and geographic investigation of severe acute respiratory syndrome coronavirus-like virus in palm civets at an animal market and on farms. J. Virol. 79, 11892\u201311900 (2005).","journal-title":"J. Virol."},{"key":"1655_CR46","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1126\/science.1092002","volume":"303","author":"CSME Consortium","year":"2004","unstructured":"Consortium, C. S. M. E. Molecular evolution of the SARS coronavirus during the course of the SARS epidemic in China. Science 303, 1666\u20131669 (2004).","journal-title":"Science"},{"key":"1655_CR47","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1093\/molbev\/msz003","volume":"36","author":"CC Weber","year":"2019","unstructured":"Weber, C. C. & Whelan, S. Physicochemical amino acid properties better describe substitution rates in large populations. Mol. Biol. Evol. 36, 679\u2013690 (2019).","journal-title":"Mol. Biol. Evol."},{"key":"1655_CR48","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.tree.2005.02.009","volume":"20","author":"ME Woolhouse","year":"2005","unstructured":"Woolhouse, M. E., Haydon, D. T. & Antia, R. Emerging pathogens: The epidemiology and evolution of species jumps. Trends Ecol. Evol. 20, 238\u2013244 (2005).","journal-title":"Trends Ecol. Evol."},{"key":"1655_CR49","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1111\/evo.12064","volume":"67","author":"JH Cuthill","year":"2013","unstructured":"Cuthill, J. H. & Charleston, M. A. A simple model explains the dynamics of preferential host switching among mammal RNA viruses. Evol. Int. J. Org. Evol. 67, 980\u2013990 (2013).","journal-title":"Evol. Int. J. Org. Evol."},{"key":"1655_CR50","doi-asserted-by":"crossref","first-page":"6984","DOI":"10.1128\/JVI.00442-08","volume":"82","author":"F Li","year":"2008","unstructured":"Li, F. Structural analysis of major species barriers between humans and palm civets for severe acute respiratory syndrome coronavirus infections. J. Virol. 82, 6984\u20136991 (2008).","journal-title":"J. Virol."},{"key":"1655_CR51","doi-asserted-by":"crossref","first-page":"11429","DOI":"10.1128\/JVI.78.20.11429-11433.2004","volume":"78","author":"W Li","year":"2004","unstructured":"Li, W. et al. Efficient replication of severe acute respiratory syndrome coronavirus in mouse cells is limited by murine angiotensin-converting enzyme 2. J. Virol. 78, 11429\u201311433 (2004).","journal-title":"J. Virol."},{"key":"1655_CR52","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nrg.2015.18","volume":"17","author":"J Echave","year":"2016","unstructured":"Echave, J., Spielman, S. J. & Wilke, C. O. Causes of evolutionary rate variation among protein sites. Nat. Rev. Genet. 17, 109 (2016).","journal-title":"Nat. Rev. Genet."},{"key":"1655_CR53","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1038\/sj.emboj.7600640","volume":"24","author":"W Li","year":"2005","unstructured":"Li, W. et al. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J. 24, 1634\u20131643 (2005).","journal-title":"EMBO J."},{"key":"1655_CR54","doi-asserted-by":"crossref","first-page":"2430","DOI":"10.1073\/pnas.0409608102","volume":"102","author":"H-D Song","year":"2005","unstructured":"Song, H.-D. et al. Cross-host evolution of severe acute respiratory syndrome coronavirus in palm civet and human. Proc. Natl. Acad. Sci. 102, 2430\u20132435 (2005).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"1655_CR55","unstructured":"Kupferschmidt, K. (American Association for the Advancement of Science, 2021)."},{"key":"1655_CR56","doi-asserted-by":"crossref","first-page":"705772","DOI":"10.3389\/fimmu.2021.705772","volume":"12","author":"MK Fath","year":"2021","unstructured":"Fath, M. K. et al. SARS-CoV-2 proteome harbors peptides which are able to trigger autoimmunity responses: implications for infection, vaccination, and population coverage. Front. Immunol. 12, 705772 (2021).","journal-title":"Front. Immunol."},{"key":"1655_CR57","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1126\/science.1092002","volume":"303","author":"Chinese, S. Molecular Epidemiology Consortium","year":"2004","unstructured":"Chinese, S. Molecular Epidemiology Consortium. Molecular evolution of the SARS coronavirus during the course of the SARS epidemic in China. Science 303, 1666\u20131669 (2004).","journal-title":"Science"},{"key":"1655_CR58","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1093\/genetics\/149.1.445","volume":"149","author":"N Goldman","year":"1998","unstructured":"Goldman, N., Thorne, J. L. & Jones, D. T. Assessing the impact of secondary structure and solvent accessibility on protein evolution. Genetics 149, 445\u2013458 (1998).","journal-title":"Genetics"},{"key":"1655_CR59","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1093\/molbev\/msp146","volume":"26","author":"EA Franzosa","year":"2009","unstructured":"Franzosa, E. A. & Xia, Y. Structural determinants of protein evolution are context-sensitive at the residue level. Mol. Biol. Evol. 26, 2387\u20132395 (2009).","journal-title":"Mol. Biol. Evol."},{"key":"1655_CR60","doi-asserted-by":"crossref","first-page":"2253","DOI":"10.1093\/molbev\/mss097","volume":"29","author":"Y Liu","year":"2012","unstructured":"Liu, Y. & Bahar, I. Sequence evolution correlates with structural dynamics. Mol. Biol. Evol. 29, 2253\u20132263 (2012).","journal-title":"Mol. Biol. Evol."},{"key":"1655_CR61","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/1471-2148-14-78","volume":"14","author":"T-T Huang","year":"2014","unstructured":"Huang, T.-T., del Valle Marcos, M. L., Hwang, J.-K. & Echave, J. A mechanistic stress model of protein evolution accounts for site-specific evolutionary rates and their relationship with packing density and flexibility. BMC Evol. Biol. 14, 78 (2014).","journal-title":"BMC Evol. Biol."},{"key":"1655_CR62","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1093\/molbev\/mst178","volume":"31","author":"S-W Yeh","year":"2014","unstructured":"Yeh, S.-W. et al. Site-specific structural constraints on protein sequence evolutionary divergence: Local packing density versus solvent exposure. Mol. Biol. Evol. 31, 135\u2013139 (2014).","journal-title":"Mol. Biol. Evol."},{"key":"1655_CR63","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1007\/s00239-014-9644-x","volume":"79","author":"A Shahmoradi","year":"2014","unstructured":"Shahmoradi, A. et al. Predicting evolutionary site variability from structure in viral proteins: Buriedness, packing, flexibility, and design. J. Mol. Evol. 79, 130\u2013142 (2014).","journal-title":"J. Mol. Evol."},{"key":"1655_CR64","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1056\/NEJMc2100362","volume":"384","author":"SS Abdool Karim","year":"2021","unstructured":"Abdool Karim, S. S. & de Oliveira, T. New SARS-CoV-2 variants\u2014Clinical, public health, and vaccine implications. N. Engl. J. Med. 384, 1866\u20131868 (2021).","journal-title":"N. Engl. J. Med."},{"key":"1655_CR65","first-page":"2100008","volume":"26","author":"A Bal","year":"2021","unstructured":"Bal, A. et al. Two-step strategy for the identification of SARS-CoV-2 variant of concern 202012\/01 and other variants with spike deletion H69\u2013V70, France, August to December 2020. Eurosurveillance 26, 2100008 (2021).","journal-title":"Eurosurveillance"},{"key":"1655_CR66","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/j.pt.2016.08.003","volume":"32","author":"A Betts","year":"2016","unstructured":"Betts, A., Rafaluk, C. & King, K. C. Host and parasite evolution in a tangled bank. Trends Parasitol. 32, 863\u2013873 (2016).","journal-title":"Trends Parasitol."},{"key":"1655_CR67","doi-asserted-by":"crossref","first-page":"4953","DOI":"10.1128\/JVI.00161-14","volume":"88","author":"A Barlan","year":"2014","unstructured":"Barlan, A. et al. Receptor variation and susceptibility to Middle East respiratory syndrome coronavirus infection. J. Virol. 88, 4953\u20134961 (2014).","journal-title":"J. Virol."},{"key":"1655_CR68","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.chom.2014.08.009","volume":"16","author":"Q Wang","year":"2014","unstructured":"Wang, Q. et al. Bat origins of MERS-CoV supported by bat coronavirus HKU4 usage of human receptor CD26. Cell Host Microbe 16, 328\u2013337 (2014).","journal-title":"Cell Host Microbe"},{"key":"1655_CR69","doi-asserted-by":"crossref","first-page":"9119","DOI":"10.1128\/JVI.01279-15","volume":"89","author":"Y Yang","year":"2015","unstructured":"Yang, Y. et al. Two mutations were critical for bat-to-human transmission of Middle East respiratory syndrome coronavirus. J. Virol. 89, 9119\u20139123 (2015).","journal-title":"J. Virol."},{"key":"1655_CR70","doi-asserted-by":"crossref","first-page":"106924","DOI":"10.1016\/j.intimp.2020.106924","volume":"88","author":"H Owji","year":"2020","unstructured":"Owji, H., Negahdaripour, M. & Hajighahramani, N. Immunotherapeutic approaches to curtail COVID-19. Int. Immunopharmacol. 88, 106924 (2020).","journal-title":"Int. Immunopharmacol."},{"key":"1655_CR71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/viro.1999.9716","volume":"258","author":"DA Steinhauer","year":"1999","unstructured":"Steinhauer, D. A. Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology 258, 1\u201320 (1999).","journal-title":"Virology"},{"key":"1655_CR72","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s00239-003-2500-z","volume":"57","author":"NG Smith","year":"2003","unstructured":"Smith, N. G. Are radical and conservative substitution rates useful statistics in molecular evolution?. J. Mol. Evol. 57, 467\u2013478 (2003).","journal-title":"J. Mol. Evol."},{"key":"1655_CR73","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/S0022-2836(03)00865-9","volume":"331","author":"EJ Snijder","year":"2003","unstructured":"Snijder, E. J. et al. Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage. J. Mol. Biol. 331, 991\u20131004 (2003).","journal-title":"J. Mol. Biol."},{"key":"1655_CR74","doi-asserted-by":"crossref","first-page":"5108","DOI":"10.1073\/pnas.0508200103","volume":"103","author":"E Minskaia","year":"2006","unstructured":"Minskaia, E. et al. Discovery of an RNA virus 3\u2032 \u2192 5\u2032 exoribonuclease that is critically involved in coronavirus RNA synthesis. Proc. Natl. Acad. Sci. 103, 5108\u20135113 (2006).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"1655_CR75","doi-asserted-by":"publisher","first-page":"5986","DOI":"10.1038\/s41467-020-19818-2","volume":"11","author":"L van Dorp","year":"2020","unstructured":"van Dorp, L. et al. No evidence for increased transmissibility from recurrent mutations in SARS-CoV-2. Nat. Commun. 11, 5986. https:\/\/doi.org\/10.1038\/s41467-020-19818-2 (2020).","journal-title":"Nat. Commun."},{"key":"1655_CR76","doi-asserted-by":"crossref","first-page":"104117","DOI":"10.1016\/j.compbiomed.2020.104117","volume":"128","author":"VK Bhardwaj","year":"2021","unstructured":"Bhardwaj, V. K., Singh, R., Das, P. & Purohit, R. Evaluation of acridinedione analogs as potential SARS-CoV-2 main protease inhibitors and their comparison with repurposed anti-viral drugs. Comput. Biol. Med. 128, 104117 (2021).","journal-title":"Comput. Biol. Med."},{"key":"1655_CR77","doi-asserted-by":"crossref","first-page":"128933","DOI":"10.1016\/j.foodchem.2020.128933","volume":"346","author":"J Sharma","year":"2021","unstructured":"Sharma, J. et al. An in-silico evaluation of different bioactive molecules of tea for their inhibition potency against non structural protein-15 of SARS-CoV-2. Food Chem. 346, 128933 (2021).","journal-title":"Food Chem."},{"key":"1655_CR78","doi-asserted-by":"crossref","first-page":"104555","DOI":"10.1016\/j.compbiomed.2021.104555","volume":"135","author":"R Singh","year":"2021","unstructured":"Singh, R., Bhardwaj, V. K., Das, P. & Purohit, R. A computational approach for rational discovery of inhibitors for non-structural protein 1 of SARS-CoV-2. Comput. Biol. Med. 135, 104555 (2021).","journal-title":"Comput. Biol. Med."},{"key":"1655_CR79","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1093\/nar\/gky092","volume":"46","author":"U Consortium","year":"2018","unstructured":"Consortium, U. UniProt: The universal protein knowledgebase. Nucleic Acids Res. 46, 2699 (2018).","journal-title":"Nucleic Acids Res."},{"key":"1655_CR80","doi-asserted-by":"crossref","first-page":"D339","DOI":"10.1093\/nar\/gky1006","volume":"47","author":"R Vita","year":"2019","unstructured":"Vita, R. et al. The immune epitope database (IEDB): 2018 update. Nucleic Acids Res. 47, D339\u2013D343 (2019).","journal-title":"Nucleic Acids Res."},{"key":"1655_CR81","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1126\/science.abb2507","volume":"367","author":"D Wrapp","year":"2020","unstructured":"Wrapp, D. et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367, 1260\u20131263 (2020).","journal-title":"Science"},{"key":"1655_CR82","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1093\/genetics\/158.3.1321","volume":"158","author":"S Kumar","year":"2001","unstructured":"Kumar, S. & Gadagkar, S. R. Disparity index: A simple statistic to measure and test the homogeneity of substitution patterns between molecular sequences. Genetics 158, 1321\u20131327 (2001).","journal-title":"Genetics"},{"key":"1655_CR83","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1093\/molbev\/msz312","volume":"37","author":"G Stecher","year":"2020","unstructured":"Stecher, G., Tamura, K. & Kumar, S. Molecular evolutionary genetics analysis (MEGA) for macOS. Mol. Biol. Evol. 37, 1237\u20131239 (2020).","journal-title":"Mol. Biol. Evol."},{"key":"1655_CR84","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1093\/molbev\/msy096","volume":"35","author":"S Kumar","year":"2018","unstructured":"Kumar, S., Stecher, G., Li, M., Knyaz, C. & Tamura, K. MEGA X: Molecular evolutionary genetics analysis across computing platforms. Mol. Biol. Evol. 35, 1547\u20131549 (2018).","journal-title":"Mol. Biol. Evol."},{"key":"1655_CR85","doi-asserted-by":"crossref","first-page":"3702","DOI":"10.1093\/bioinformatics\/bth444","volume":"20","author":"T Frickey","year":"2004","unstructured":"Frickey, T. & Lupas, A. CLANS: A Java application for visualizing protein families based on pairwise similarity. Bioinformatics 20, 3702\u20133704 (2004).","journal-title":"Bioinformatics"},{"key":"1655_CR86","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1006\/jmbi.2000.4042","volume":"302","author":"C Notredame","year":"2000","unstructured":"Notredame, C., Higgins, D. G. & Heringa, J. T-Coffee: A novel method for fast and accurate multiple sequence alignment. J. Mol. Biol. 302, 205\u2013217 (2000).","journal-title":"J. Mol. Biol."},{"key":"1655_CR87","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.jmb.2017.12.007","volume":"430","author":"L Zimmermann","year":"2018","unstructured":"Zimmermann, L. et al. A completely reimplemented MPI bioinformatics toolkit with a new HHpred server at its core. J. Mol. Biol. 430, 2237\u20132243 (2018).","journal-title":"J. Mol. Biol."},{"key":"1655_CR88","volume":"5","author":"RF Schwarz","year":"2010","unstructured":"Schwarz, R. F. et al. Evolutionary distances in the twilight zone\u2014A rational kernel approach. PLoS ONE 5, e15788 (2010).","journal-title":"PLoS ONE"},{"key":"1655_CR89","unstructured":"Jaakkola, T. S., Diekhans, M. & Haussler, D. Using the Fisher kernel method to detect remote protein homologies. ISMB. 149\u2013158 (1999)."},{"key":"1655_CR90","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9780511790492","volume-title":"Biological Sequence Analysis","author":"R Durbin","year":"1998","unstructured":"Durbin, R., Eddy, S., Krogh, A. & Mitchison, G. Biological Sequence Analysis (Cambridge University Press, 1998)."},{"key":"1655_CR91","doi-asserted-by":"crossref","first-page":"W430","DOI":"10.1093\/nar\/gkw306","volume":"44","author":"S Wang","year":"2016","unstructured":"Wang, S., Li, W., Liu, S. & Xu, J. RaptorX-Property: A web server for protein structure property prediction. Nucleic Acids Res. 44, W430\u2013W435 (2016).","journal-title":"Nucleic Acids Res."},{"key":"1655_CR92","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1093\/bioinformatics\/16.4.404","volume":"16","author":"LJ McGuffin","year":"2000","unstructured":"McGuffin, L. J., Bryson, K. & Jones, D. T. The PSIPRED protein structure prediction server. Bioinformatics 16, 404\u2013405 (2000).","journal-title":"Bioinformatics"},{"key":"1655_CR93","doi-asserted-by":"crossref","first-page":"W320","DOI":"10.1093\/nar\/gkx246","volume":"45","author":"M Baek","year":"2017","unstructured":"Baek, M., Park, T., Heo, L., Park, C. & Seok, C. GalaxyHomomer: A web server for protein homo-oligomer structure prediction from a monomer sequence or structure. Nucleic Acids Res. 45, W320\u2013W324 (2017).","journal-title":"Nucleic Acids Res."},{"key":"1655_CR94","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/nature16988","volume":"531","author":"AC Walls","year":"2016","unstructured":"Walls, A. C. et al. Cryo-electron microscopy structure of a coronavirus spike glycoprotein trimer. Nature 531, 114\u2013117 (2016).","journal-title":"Nature"},{"key":"1655_CR95","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.tibs.2011.01.002","volume":"36","author":"NT Doncheva","year":"2011","unstructured":"Doncheva, N. T., Klein, K., Domingues, F. S. & Albrecht, M. Analyzing and visualizing residue networks of protein structures. Trends Biochem. Sci. 36, 179\u2013182 (2011).","journal-title":"Trends Biochem. Sci."},{"key":"1655_CR96","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","volume":"13","author":"P Shannon","year":"2003","unstructured":"Shannon, P. et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498\u20132504 (2003).","journal-title":"Genome Res."},{"key":"1655_CR97","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","volume":"25","author":"EF Pettersen","year":"2004","unstructured":"Pettersen, E. F. et al. UCSF Chimera\u2014A visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605\u20131612 (2004).","journal-title":"J. Comput. Chem."},{"key":"1655_CR98","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1093\/bioinformatics\/btx586","volume":"34","author":"G Brysbaert","year":"2018","unstructured":"Brysbaert, G., Lorgouilloux, K., Vranken, W. F. & Lensink, M. F. RINspector: A Cytoscape app for centrality analyses and DynaMine flexibility prediction. Bioinformatics 34, 294\u2013296 (2018).","journal-title":"Bioinformatics"},{"key":"1655_CR99","doi-asserted-by":"crossref","first-page":"2006.0019","DOI":"10.1038\/msb4100063","volume":"2","author":"A del Sol","year":"2006","unstructured":"del Sol, A., Fujihashi, H., Amoros, D. & Nussinov, R. Residues crucial for maintaining short paths in network communication mediate signaling in proteins. Mol. Syst. Biol. 2, 2006.0019 (2006).","journal-title":"Mol. Syst. Biol."},{"key":"1655_CR100","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1126\/science.abb7269","volume":"368","author":"M Yuan","year":"2020","unstructured":"Yuan, M. et al. A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV. Science 368, 630\u2013633 (2020).","journal-title":"Science"},{"key":"1655_CR101","doi-asserted-by":"crossref","first-page":"11196","DOI":"10.1073\/pnas.1613630113","volume":"113","author":"SO Dahms","year":"2016","unstructured":"Dahms, S. O., Arciniega, M., Steinmetzer, T., Huber, R. & Than, M. E. Structure of the unliganded form of the proprotein convertase furin suggests activation by a substrate-induced mechanism. Proc. Natl. Acad. Sci. 113, 11196\u201311201 (2016).","journal-title":"Proc. Natl. Acad. Sci."},{"key":"1655_CR102","doi-asserted-by":"crossref","first-page":"e24657","DOI":"10.1371\/journal.pone.0024657","volume":"6","author":"BG Pierce","year":"2011","unstructured":"Pierce, B. G., Hourai, Y. & Weng, Z. Accelerating protein docking in ZDOCK using an advanced 3D convolution library. PLoS\u00a0One 6, e24657 (2011).","journal-title":"PLoS\u00a0One"},{"key":"1655_CR103","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1385\/1-59259-890-0:571","volume-title":"The Proteomics Protocols Handbook","author":"E Gasteiger","year":"2005","unstructured":"Gasteiger, E. et al. The Proteomics Protocols Handbook 571\u2013607 (Springer, 2005)."},{"key":"1655_CR104","doi-asserted-by":"crossref","first-page":"3506","DOI":"10.1093\/bioinformatics\/btv472","volume":"31","author":"J Ma","year":"2015","unstructured":"Ma, J., Wang, S., Wang, Z. & Xu, J. Protein contact prediction by integrating joint evolutionary coupling analysis and supervised learning. Bioinformatics 31, 3506\u20133513 (2015).","journal-title":"Bioinformatics"},{"key":"1655_CR105","volume":"13","author":"S Wang","year":"2017","unstructured":"Wang, S., Sun, S., Li, Z., Zhang, R. & Xu, J. Accurate de novo prediction of protein contact map by ultra-deep learning model. PLoS Comput. Biol. 13, e1005324 (2017).","journal-title":"PLoS Comput. Biol."},{"key":"1655_CR106","doi-asserted-by":"crossref","first-page":"3701","DOI":"10.1038\/sj.emboj.7600378","volume":"23","author":"B Ritter","year":"2004","unstructured":"Ritter, B. et al. Two WXXF-based motifs in NECAPs define the specificity of accessory protein binding to AP-1 and AP-2. EMBO J. 23, 3701\u20133710 (2004).","journal-title":"EMBO J."},{"key":"1655_CR107","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/978-1-4939-6406-2_20","volume-title":"Prediction of Protein Secondary Structure","author":"B Ligeti","year":"2017","unstructured":"Ligeti, B., Vera, R., Juh\u00e1sz, J. & Pongor, S. Prediction of Protein Secondary Structure 301\u2013309 (Springer, 2017)."},{"key":"1655_CR108","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/gch2.1018","volume":"1","author":"S Elbe","year":"2017","unstructured":"Elbe, S. & Buckland-Merrett, G. Data, disease and diplomacy: GISAID\u2019s innovative contribution to global health. Glob. Chall. 1, 33\u201346 (2017).","journal-title":"Glob. Chall."},{"key":"1655_CR109","first-page":"30494","volume":"22","author":"Y Shu","year":"2017","unstructured":"Shu, Y. & McCauley, J. GISAID: Global initiative on sharing all influenza data\u2014From vision to reality. Eurosurveillance 22, 30494 (2017).","journal-title":"Eurosurveillance"},{"key":"1655_CR110","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1126\/science.185.4154.862","volume":"185","author":"R Grantham","year":"1974","unstructured":"Grantham, R. Amino acid difference formula to help explain protein evolution. Science 185, 862\u2013864 (1974).","journal-title":"Science"},{"key":"1655_CR111","unstructured":"DeLano, W. L. The PyMOL molecular graphics system. Accessed 14 Apr 2021. http:\/\/www.pymol.org (2002)."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-01655-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-01655-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-01655-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T18:16:23Z","timestamp":1670091383000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-01655-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,8]]},"references-count":111,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["1655"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-01655-y","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,8]]},"assertion":[{"value":"24 July 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 November 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 December 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"23622"}}