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Several studies showed that the glycosylation of virus spike (S) protein and the Angiotensin-Converting Enzyme 2 (ACE2) receptor on the host cell is critical for the virus infectivity. Molecular Dynamics (MD) simulations were used to explore the role of a novel mutated O-glycosylation site (D494S) on the Receptor Binding Domain (RBD) of S protein. This site was suggested as a key mediator of virus-host interaction. By exploring the dynamics of three O-glycosylated models and the control systems of unglcosylated S4944 and S494D complexes, it was shown that the decoration of S494 with elongated O-glycans results in stabilized interactions on the direct RBD-ACE2. Calculation of the distances between RBD and two major H1, H2 helices of ACE2 and the interacting pairs of amino acids in the interface showed that the elongated O-glycan maintains these interactions by forming several polar contacts with the neighbouring residues while it would not interfere in the direct binding interface. Relative binding free energy of RBD-ACE2 is also more favorable in the O-glycosylated models with longer glycans. The increase of RBD binding affinity to ACE2 depends on the size of attached O-glycan. By increasing the size of O-glycan, the RBD-ACE2 binding affinity will increase. Hence, this crucial factor must be taken into account for any further inhibitory approaches towards RBD-ACE2 interaction.<\/jats:p>","DOI":"10.1038\/s41598-021-94602-w","type":"journal-article","created":{"date-parts":[[2021,7,26]],"date-time":"2021-07-26T06:10:53Z","timestamp":1627279853000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["S494 O-glycosylation site on the SARS-CoV-2 RBD affects the virus affinity to ACE2 and its infectivity; a molecular dynamics study"],"prefix":"10.1038","volume":"11","author":[{"given":"Shadi","family":"Rahnama","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maryam","family":"Azimzadeh Irani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehriar","family":"Amininasab","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammad Reza","family":"Ejtehadi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,7,26]]},"reference":[{"key":"94602_CR1","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1038\/s41591-020-0820-9","volume":"26","author":"KG Andersen","year":"2020","unstructured":"Andersen, K. 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