Contrasting the effect of hinge region insertions and non-active site mutations on HIV protease-inhibitor interactions: Insights from altered flap dynamics.

Autor: Mokhantso T; Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, 2050, South Africa., Sherry D; Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, 2050, South Africa., Worth R; Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, 2050, South Africa., Pandian R; Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, 2050, South Africa., Achilonu I; Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, 2050, South Africa., Sayed Y; Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of the Witwatersrand, Johannesburg, 2050, South Africa. Electronic address: yasien.sayed@wits.ac.za.
Jazyk: angličtina
Zdroj: Journal of molecular graphics & modelling [J Mol Graph Model] 2024 Dec; Vol. 133, pp. 108850. Date of Electronic Publication: 2024 Aug 29.
DOI: 10.1016/j.jmgm.2024.108850
Abstrakt: HIV-1 protease (PR) enzyme is a viable antiretroviral drug target due to its crucial role in HIV maturation. Over many decades, the HIV-1 PR enzyme has exhibited mutations brought on by drug pressure and error-prone nature of HIV-1 reverse transcriptase. Non-active site mutations have played a pivotal role in drug resistance; however, their mechanism of action has not been fully elucidated. We investigated how non-active site mutations affect the conformational stability and drug binding ability of HIV-1 PR. In light of this, we studied a novel HIV-1 subtype C protease variant containing an insertion of valine (↑V) in the hinge region. We analysed the mutations in the presence and absence of ten background mutations. Molecular dynamics simulations revealed that both with and without the background mutations, the PR exhibited increased flexibility of hinge, flaps and fulcrum regions. This allowed the PR to adopt a wider flap conformation when in complex with several inhibitors. Additionally, the simulations revealed that the protease inhibitors (PIs) could not bring the mutated variant proteases into a stable, closed conformation, resulting in increased solvent exposure of the inhibitors. Together, these results suggest that the mutations decrease the favourability of binding by altering the dynamics of the flap regions. Notably, the insertion mutation increased PR hinge flexibility and the introduction of background mutations compensated for this by stabilising the cantilever and hinge regions. Together, these findings provide insight into how non-active site mutations affect PR conformational dynamics in critical areas of the PR thus impacting on drug binding capacity and potentially contributing to drug resistance.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yasien Sayed reports financial support was provided by University of the WitwatersrandJohannesburg School of Molecular and Cell Biology. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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