Molecular dynamic simulations to investigate the structural impact of known drug resistance mutations on HIV-1C integrase-dolutegravir binding

dc.contributor.authorChitongo, Rumbidzai
dc.contributor.authorObasa, Adetayo Emmanuel
dc.contributor.authorMikasi, Sello Given
dc.date.accessioned2021-01-21T09:55:57Z
dc.date.available2021-01-21T09:55:57Z
dc.date.issued2020
dc.description.abstractResistance associated mutations (RAMs) threaten the long-term success of combination antiretroviral therapy (cART) outcomes for HIV-1 treatment. HIV-1 Integrase (IN) strand transfer inhibitors (INSTIs) have proven to be a viable option for highly specific HIV-1 therapy. The INSTI, Dolutegravir is recommended by the World Health Organization for use as first-line cART. This study aims to understand how RAMs affect the stability of IN, as well as the binding of the drug Dolutegravir to the catalytic pocket of the protein. A homology model of HIV-1 subtype C IN was successfully constructed and validated. The site directed mutator webserver was used to predict destabilizing and/or stabilizing effects of known RAMs while FoldX confirmed any changes in protein energy upon introduction of mutation. Also, interaction analysis was performed between neighbouring residues. Three mutations known to be associated with Raltegravir, Elvitegravir and Dolutegravir resistance were selected; E92Q, G140S and Y143R, for molecular dynamics simulations. The structural quality assessment indicated high reliability of the HIV-1C IN tetrameric structure, with more than 90% confidence in modelled regions. Change in free energy for the three mutants indicated different effects, while simulation analysis showed G140S to have the largest affect on protein stability and flexibility.en_US
dc.identifier.citationChitongo, R. et al. (2020). Molecular dynamic simulations to investigate the structural impact of known drug resistance mutations on HIV-1C integrase-dolutegravir binding. PLoS ONE ,15(5),e0223464en_US
dc.identifier.issn1932-6203
dc.identifier.uri10.1371/journal.pone.0223464
dc.identifier.urihttp://hdl.handle.net/10566/5713
dc.language.isoenen_US
dc.publisherPublic Library of Scienceen_US
dc.subjectHIV-1Cen_US
dc.subjectIntegrase-Dolutegravir bindingen_US
dc.subjectDrug resistanceen_US
dc.subjectAntiretroviral therapyen_US
dc.subjectSouth Africaen_US
dc.titleMolecular dynamic simulations to investigate the structural impact of known drug resistance mutations on HIV-1C integrase-dolutegravir bindingen_US
dc.typeArticleen_US

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