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dc.contributor.authorBastys, Tomas
dc.contributor.authorGapsys, Vytautas
dc.contributor.authorWalter, Hauke
dc.contributor.authorHeger, Eva
dc.contributor.authorDoncheva, Nadezhda T
dc.contributor.authorKaiser, Rolf
dc.contributor.authorde Groot, Bert L
dc.contributor.authorKalinina, Olga V
dc.date.accessioned2020-08-07T09:04:42Z
dc.date.available2020-08-07T09:04:42Z
dc.date.issued2020-05-19
dc.identifier.citationRetrovirology. 2020;17(1):13. Published 2020 May 19. doi:10.1186/s12977-020-00520-6.en_US
dc.identifier.pmid32430025
dc.identifier.doi10.1186/s12977-020-00520-6
dc.identifier.urihttp://hdl.handle.net/10033/622393
dc.description.abstractBackground: HIV-1 can develop resistance to antiretroviral drugs, mainly through mutations within the target regions of the drugs. In HIV-1 protease, a majority of resistance-associated mutations that develop in response to therapy with protease inhibitors are found in the protease's active site that serves also as a binding pocket for the protease inhibitors, thus directly impacting the protease-inhibitor interactions. Some resistance-associated mutations, however, are found in more distant regions, and the exact mechanisms how these mutations affect protease-inhibitor interactions are unclear. Furthermore, some of these mutations, e.g. N88S and L76V, do not only induce resistance to the currently administered drugs, but contrarily induce sensitivity towards other drugs. In this study, mutations N88S and L76V, along with three other resistance-associated mutations, M46I, I50L, and I84V, are analysed by means of molecular dynamics simulations to investigate their role in complexes of the protease with different inhibitors and in different background sequence contexts. Results: Using these simulations for alchemical calculations to estimate the effects of mutations M46I, I50L, I84V, N88S, and L76V on binding free energies shows they are in general in line with the mutations' effect on [Formula: see text] values. For the primary mutation L76V, however, the presence of a background mutation M46I in our analysis influences whether the unfavourable effect of L76V on inhibitor binding is sufficient to outweigh the accompanying reduction in catalytic activity of the protease. Finally, we show that L76V and N88S changes the hydrogen bond stability of these residues with residues D30/K45 and D30/T31/T74, respectively. Conclusions: We demonstrate that estimating the effect of both binding pocket and distant mutations on inhibitor binding free energy using alchemical calculations can reproduce their effect on the experimentally measured [Formula: see text] values. We show that distant site mutations L76V and N88S affect the hydrogen bond network in the protease's active site, which offers an explanation for the indirect effect of these mutations on inhibitor binding. This work thus provides valuable insights on interplay between primary and background mutations and mechanisms how they affect inhibitor binding.en_US
dc.language.isoenen_US
dc.publisherBMCen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectAlchemical binding free energy change calculationen_US
dc.subjectDistant site mutationsen_US
dc.subjectHIV-1 protease inhibitorsen_US
dc.subjectHydrogen bond network perturbationen_US
dc.subjectResistance-associated mutationsen_US
dc.titleNon-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors.en_US
dc.typeArticleen_US
dc.typeOtheren_US
dc.identifier.eissn1742-4690
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
dc.identifier.journalRetrovirologyen_US
dc.source.volume17
dc.source.issue1
dc.source.beginpage13
dc.source.endpage
refterms.dateFOA2020-08-07T09:04:42Z
dc.source.journaltitleRetrovirology
dc.source.countryInternational
dc.source.countryInternational
dc.source.countryEngland


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