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However, this task is still challenging, because a detailed understanding of the underlying molecular processes, mediated by the key cellular proteases TMPRSS2 and furin, is still lacking. Here, we show by large-scale atomistic calculations that binding of the ACE2 cell receptor at one of the heteromers of the SARS-CoV-2 spike leads to a release of its furin cleavage site (S1\/S2), enabling an enhanced furin binding, and that this latter process promotes the binding of TMPRSS2 through the release of the TMPRSS2 cleavage site (S2\u2032) out of the ACE2-binding heteromer. Moreover, we find that, after proteolytic cleavage, improved furin binding causes that parts of the S2 subunit dissociate from the complex, suggesting that furin promotes the fusion of the S2 subunit with the cell membrane before transfer of the viral RNA.<\/jats:p>\n                <jats:p><jats:bold>Graphical abstract<\/jats:bold><\/jats:p>\n                <jats:p>Here we show by computational means that binding of the ACE2-cell receptor at one of the heteromers of the SARS-CoV-2 spike leads to an enhanced binding of the protease furin, promoting the binding of the protease TMPRSS2. Moreover, we show that, after proteolytic cleavage, improved furin binding causes that parts of the heteromer dissociate from the spike.<\/jats:p>","DOI":"10.1007\/s00894-022-05206-8","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T18:02:45Z","timestamp":1658253765000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Study of protease-mediated processes initiating viral infection and cell\u2013cell viral spreading of SARS-CoV-2"],"prefix":"10.1007","volume":"28","author":[{"given":"Thanawat","family":"Thaingtamtanha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7565-0997","authenticated-orcid":false,"given":"Stephan A.","family":"Baeurle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,19]]},"reference":[{"key":"5206_CR1","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1038\/s41591-020-0863-y","volume":"26","author":"M McKee","year":"2020","unstructured":"McKee M, Stuckler D (2020) If the world fails to protect the economy, COVID-19 will damage health not just now but also in the future. 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