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Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors

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  • معلومة اضافية
    • Publication Information:
      BMC, 2020.
    • Publication Date:
      2020
    • Collection:
      LCC:Immunologic diseases. Allergy
    • Abstract:
      Abstract Background 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 $$IC_{50}$$ I C 50 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 $$IC_{50}$$ I C 50 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.
    • File Description:
      electronic resource
    • ISSN:
      1742-4690
    • Relation:
      http://link.springer.com/article/10.1186/s12977-020-00520-6; https://doaj.org/toc/1742-4690
    • Accession Number:
      10.1186/s12977-020-00520-6
    • Rights:
      Journal Licence: CC BY
    • Accession Number:
      edsdoj.7e14234516e447aa8834a2af7952a526
  • Citations
    • ABNT:
      TOMAS BASTYS et al. Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors. Retrovirology, [s. l.], v. 17, n. 1, p. 1–14, 2020. DOI 10.1186/s12977-020-00520-6. Disponível em: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edsdoj&AN=edsdoj.7e14234516e447aa8834a2af7952a526&custid=s8280428. Acesso em: 11 jul. 2020.
    • AMA:
      Tomas Bastys, Vytautas Gapsys, Hauke Walter, et al. Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors. Retrovirology. 2020;17(1):1-14. doi:10.1186/s12977-020-00520-6.
    • AMA11:
      Tomas Bastys, Vytautas Gapsys, Hauke Walter, et al. Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors. Retrovirology. 2020;17(1):1-14. doi:10.1186/s12977-020-00520-6
    • APA:
      Tomas Bastys, Vytautas Gapsys, Hauke Walter, Eva Heger, Nadezhda T. Doncheva, Rolf Kaiser, Bert L. de Groot, & Olga V. Kalinina. (2020). Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors. Retrovirology, 17(1), 1–14. https://doi.org/10.1186/s12977-020-00520-6
    • Chicago/Turabian: Author-Date:
      Tomas Bastys, Vytautas Gapsys, Hauke Walter, Eva Heger, Nadezhda T. Doncheva, Rolf Kaiser, Bert L. de Groot, and Olga V. Kalinina. 2020. “Non-Active Site Mutants of HIV-1 Protease Influence Resistance and Sensitisation towards Protease Inhibitors.” Retrovirology 17 (1): 1–14. doi:10.1186/s12977-020-00520-6.
    • Harvard:
      Tomas Bastys et al. (2020) ‘Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors’, Retrovirology, 17(1), pp. 1–14. doi: 10.1186/s12977-020-00520-6.
    • Harvard: Australian:
      Tomas Bastys, Vytautas Gapsys, Hauke Walter, Eva Heger, Nadezhda T. Doncheva, Rolf Kaiser, Bert L. de Groot & Olga V. Kalinina 2020, ‘Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors’, Retrovirology, vol. 17, no. 1, pp. 1–14, viewed 11 July 2020, .
    • MLA:
      Tomas Bastys, et al. “Non-Active Site Mutants of HIV-1 Protease Influence Resistance and Sensitisation towards Protease Inhibitors.” Retrovirology, vol. 17, no. 1, May 2020, pp. 1–14. EBSCOhost, doi:10.1186/s12977-020-00520-6.
    • Chicago/Turabian: Humanities:
      Tomas Bastys, Vytautas Gapsys, Hauke Walter, Eva Heger, Nadezhda T. Doncheva, Rolf Kaiser, Bert L. de Groot, and Olga V. Kalinina. “Non-Active Site Mutants of HIV-1 Protease Influence Resistance and Sensitisation towards Protease Inhibitors.” Retrovirology 17, no. 1 (May 1, 2020): 1–14. doi:10.1186/s12977-020-00520-6.
    • Vancouver/ICMJE:
      Tomas Bastys, Vytautas Gapsys, Hauke Walter, Eva Heger, Nadezhda T. Doncheva, Rolf Kaiser, et al. Non-active site mutants of HIV-1 protease influence resistance and sensitisation towards protease inhibitors. Retrovirology [Internet]. 2020 May 1 [cited 2020 Jul 11];17(1):1–14. Available from: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edsdoj&AN=edsdoj.7e14234516e447aa8834a2af7952a526&custid=s8280428