Evidence map›Paper›PMID 38918875›Full record

ArticleVirology journal2024

Impact of subtype C-specific amino acid variants on HIV-1 Tat-TAR interaction: insights from molecular modelling and dynamics.

Piwai T Gotora, Keaghan Brown, Darius R Martin, Rencia van der Sluis, Ruben Cloete, Monray E Williams

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Article in Virology journal, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

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5citing papers in PubMed
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3 · Its place in the literature

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5 citing papers in PubMed.

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5 · Who and what money

Authors and funding

6 authors.

Piwai T Gotora *Human Metabolomics, North-West University, Potchefstroom, South Africa.
Keaghan Brown *South African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Bellville, South Africa.
Darius R MartinSouth African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Bellville, South Africa.
Rencia van der SluisHuman Metabolomics, North-West University, Potchefstroom, South Africa.
Ruben CloeteSouth African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Bellville, South Africa.
Monray E WilliamsHuman Metabolomics, North-West University, Potchefstroom, South Africa. Monray.Williams@nwu.ac.za.

Funding

National Research Foundation TTK22031652Poliomyelitis Research Foundation 23/84
6 · The paper itself

Abstract

backgroundHIV-1 produces Tat, a crucial protein for transcription, viral replication, and CNS neurotoxicity. Tat interacts with TAR, enhancing HIV reverse transcription. Subtype C Tat variants (C31S, R57S, Q63E) are associated with reduced transactivation and neurovirulence compared to subtype B. However, their precise impact on Tat-TAR binding is unclear. This study investigates how these substitutions affect Tat-TAR interaction.

methodsWe utilized molecular modelling techniques, including MODELLER, to produce precise three-dimensional structures of HIV-1 Tat protein variants. We utilized Tat subtype B as the reference or wild type, and generated Tat variants to mirror those amino acid variants found in Tat subtype C. Subtype C-specific amino acid substitutions were selected based on their role in the neuropathogenesis of HIV-1. Subsequently, we conducted molecular docking of each Tat protein variant to TAR using HDOCK, followed by molecular dynamic simulations.

resultsMolecular docking results indicated that Tat subtype B (TatWt) showed the highest affinity for the TAR element (-262.07), followed by TatC31S (-261.61), TatQ63E (-256.43), TatC31S/R57S/Q63E (-238.92), and TatR57S (-222.24). However, binding free energy analysis showed higher affinities for single variants TatQ63E (-349.2 ± 10.4 kcal/mol) and TatR57S (-290.0 ± 9.6 kcal/mol) compared to TatWt (-247.9 ± 27.7 kcal/mol), while TatC31S and TatC31S/R57SQ/63E showed lower values. Interactions over the protein trajectory were also higher for TatQ63E and TatR57S compared to TatWt, TatC31S, and TatC31S/R57SQ/63E, suggesting that modifying amino acids within the Arginine/Glutamine-rich region notably affects TAR interaction. Single amino acid mutations TatR57S and TatQ63E had a significant impact, while TatC31S had minimal effect. Introducing single amino acid variants from TatWt to a more representative Tat subtype C (TatC31S/R57SQ/63E) resulted in lower predicted binding affinity, consistent with previous findings.

conclusionsThese identified amino acid positions likely contribute significantly to Tat-TAR interaction and the differential pathogenesis and neuropathogenesis observed between subtype B and subtype C. Additional experimental investigations should prioritize exploring the influence of these amino acid signatures on TAR binding to gain a comprehensive understanding of their impact on viral transactivation, potentially identifying them as therapeutic targets.

Indexed as

Amino Acid SubstitutionHIV-1Molecular Dynamics SimulationProtein Bindingtat Gene Products, Human Immunodeficiency VirusAmino AcidsHIV Long Terminal RepeatHumansModels, MolecularMolecular Docking SimulationAmino Acidstat Gene Products, Human Immunodeficiency VirusHIV-associated neurocognitive disordersMolecular dockingMolecular dynamic simulationMolecular modellingSubtype BSubtype CTat polymorphisms

Identifiers

PMID38918875
PMCPMC11202254

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