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A crucial process for viral infection, and thus a target for developing antiviral drugs, is the uncoating of the viral genome. Here a force spectroscopy procedure using an atomic force microscope is implemented to study uncoating for individual human rhinovirus particles. Application of an increasing mechanical force on a virion led to a high force\u2010induced structural transition that facilitated extrusion of the viral RNA molecule without loss of capsid integrity. Application of force to virions that h ad previously extruded the RNA, or to RNA\u2010free capsids, led to a lower force\u2010induced event associated with capsid disruption. The kinetic parameters are determined for each reaction. The high\u2010force event is a stochastic process governed by a moderate free energy barrier (\u224820\u00a0kcal\u00a0mol<jats:sup>\u22121<\/jats:sup>), which results in a heterogeneous population of structurally weakened virions in which different fractions of the RNA molecule are externalized. The effects of antiviral compounds or capsid mutation on the kinetics of this reaction reveal a correlation between the reaction rate and virus infectivity.<\/jats:p>","DOI":"10.1002\/smll.202304722","type":"journal-article","created":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T23:24:57Z","timestamp":1697066697000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Single\u2010Molecule Analysis of Genome Uncoating from Individual Human Rhinovirus Particles, and Modulation by Antiviral Drugs"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6801-640X","authenticated-orcid":false,"given":"Alejandro","family":"Valbuena","sequence":"first","affiliation":[{"name":"Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d (CSIC\u2010UAM) Universidad Aut\u00f3noma de Madrid  28049 Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klara","family":"Strobl","sequence":"additional","affiliation":[{"name":"Departamento de F\u00edsica de la Materia Condensada Universidad Aut\u00f3noma de Madrid  28049 Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4797-7033","authenticated-orcid":false,"given":"Juan Carlos","family":"Gil\u2010Redondo","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d (CSIC\u2010UAM) Universidad Aut\u00f3noma de Madrid  28049 Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Valiente","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d (CSIC\u2010UAM) Universidad Aut\u00f3noma de Madrid  28049 Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2386-3186","authenticated-orcid":false,"given":"Pedro J.","family":"de Pablo","sequence":"additional","affiliation":[{"name":"Departamento de F\u00edsica de la Materia Condensada Universidad Aut\u00f3noma de Madrid  28049 Madrid Spain"},{"name":"Instituto de F\u00edsica de la Materia Condensada (IFIMAC) Universidad Aut\u00f3noma de Madrid  28049 Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2915-1529","authenticated-orcid":false,"given":"Mauricio G.","family":"Mateu","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular \u201cSevero Ochoa\u201d (CSIC\u2010UAM) Universidad Aut\u00f3noma de Madrid  28049 Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10,8]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-3233(03)01005-2"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/v12060618"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4614-0980-9"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-007-6552-8"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-007-6552-8_15"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12387"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-virology-092818-015550"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/82_2010_37"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/9781555816698"},{"key":"e_1_2_9_10_1","first-page":"369","volume-title":"The Picornaviruses","author":"Hershenson M. 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