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Acidification triggers a large conformational change in the fusion protein, hemagglutinin (HA), which enables the insertion of the N-terminal region of the HA2 subunit, known as the fusion peptide, into the membrane of the host endosome. However, the mechanism by which pH modulates the molecular properties of the fusion peptide remains unclear. To answer this question, we performed the first constant-pH molecular dynamics simulations of the influenza fusion peptide in a membrane, extending for 40\u00a0\u00b5s of aggregated time. The simulations were combined with spectroscopic data, which showed that the peptide is twofold more active in promoting lipid mixing of model membranes at pH 5 than at pH 7.4. The realistic treatment of protonation introduced by the constant-pH molecular dynamics simulations revealed that low pH stabilizes a vertical membrane-spanning conformation and leads to more frequent contacts between the fusion peptide and the lipid headgroups, which may explain the increase in activity. The study also revealed that the N-terminal region is determinant for the peptide\u2019s effect on the membrane.<\/jats:p>","DOI":"10.1038\/s41598-020-77040-y","type":"journal-article","created":{"date-parts":[[2020,11,18]],"date-time":"2020-11-18T11:05:54Z","timestamp":1605697554000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Effect of pH on the influenza fusion peptide properties unveiled by constant-pH molecular dynamics simulations combined with experiment"],"prefix":"10.1038","volume":"10","author":[{"given":"Diana","family":"Lousa","sequence":"first","affiliation":[]},{"given":"Ant\u00f3nia R. T.","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"Sara R. 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