Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.csbj.2020.12.022
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dc.titleThe impact of Gag non-cleavage site mutations on HIV-1 viral fitness from integrative modelling and simulations
dc.contributor.authorSamsudin, Firdaus
dc.contributor.authorGan, Samuel Ken-En
dc.contributor.authorBond, Peter J.
dc.date.accessioned2022-10-13T07:57:56Z
dc.date.available2022-10-13T07:57:56Z
dc.date.issued2021-01-01
dc.identifier.citationSamsudin, Firdaus, Gan, Samuel Ken-En, Bond, Peter J. (2021-01-01). The impact of Gag non-cleavage site mutations on HIV-1 viral fitness from integrative modelling and simulations. Computational and Structural Biotechnology Journal 19 : 330-342. ScholarBank@NUS Repository. https://doi.org/10.1016/j.csbj.2020.12.022
dc.identifier.issn2001-0370
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/233273
dc.description.abstractThe high mutation rate in retroviruses is one of the leading causes of drug resistance. In human immunodeficiency virus type-1 (HIV-1), synergistic mutations in its protease and the protease substrate – the Group-specific antigen (Gag) polyprotein – work together to confer drug resistance against protease inhibitors and compensate the mutations affecting viral fitness. Some Gag mutations can restore Gag-protease binding, yet most Gag-protease correlated mutations occur outside of the Gag cleavage site. To investigate the molecular basis for this, we now report multiscale modelling approaches to investigate various sequentially cleaved Gag products in the context of clinically relevant mutations that occur outside of the cleavage sites, including simulations of the largest Gag proteolytic product in its viral membrane-bound state. We found that some mutations, such as G123E and H219Q, involve direct interaction with cleavage site residues to influence their local environment, while certain mutations in the matrix domain lead to the enrichment of lipids important for Gag targeting and assembly. Collectively, our results reveal why non-cleavage site mutations have far-reaching implications outside of Gag proteolysis, with important consequences for drugging Gag maturation intermediates and tackling protease inhibitor resistance. © 2020 The Author(s)
dc.publisherElsevier B.V.
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceScopus OA2021
dc.subjectGroup-specific antigen (Gag)
dc.subjectHIV-1
dc.subjectIntegrative modelling
dc.subjectMultiscale simulation
dc.subjectProtease inhibitor drug resistance
dc.typeArticle
dc.contributor.departmentDEPT OF BIOLOGICAL SCIENCES
dc.description.doi10.1016/j.csbj.2020.12.022
dc.description.sourcetitleComputational and Structural Biotechnology Journal
dc.description.volume19
dc.description.page330-342
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