{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T15:23:22Z","timestamp":1789140202745,"version":"build-2803163510"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T00:00:00Z","timestamp":1649289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>HIV-1 is responsible for a spectrum of neurocognitive deficits defined as HIV-associated neurocognitive disorders (HAND). The HIV transactivator of transcription (Tat) protein plays a key role in the neuropathophysiology of HAND. The Tat protein functions by transactivation of viral genes through its interaction with the transactivation response (TAR) RNA element. Subtype-specific Tat protein signatures including C31S, R57S and Q63E present in Tat subtype C has previously been linked to a lowered neuropathophysiology compared to Tat subtype B. In this study, we attempted to understand the molecular mechanism by which Tat subtype-specific variation, particularly, C31S, R57S, and Q63E influence the Tat-TAR interaction. We performed molecular modeling to generate accurate three-dimensional protein structures of the HIV-1 Tat subtypes C and B using the Swiss model webserver. Thereafter, we performed a molecular docking of the TAR RNA element to each of the Tat subtypes B and C protein structures using the HDOCK webserver. Our findings indicate that Tat subtype B had a higher affinity for the TAR RNA element compared to Tat subtype C based on a higher docking score of \u2212187.37, a higher binding free energy value of \u22129834.63\u2009\u00b1\u2009216.17\u2009kJ\/mol, and a higher number of protein\u2013nucleotide interactions of 26. Furthermore, Tat subtype B displayed more flexible regions when bound to the TAR element and this flexibility could account for the stronger affinity of Tat subtype B to TAR. From the Tat signatures linked to neuropathogenesis, only R57\/R57S are involved in Tat-TAR interaction. Due to the lack of electrostatic interactions observed between Tat subtype C and TAR, weaker affinity is observed, and this may contribute to a lower level of neuropathophysiology observed in subtype C infection.<\/jats:p>","DOI":"10.3389\/fmicb.2022.866611","type":"journal-article","created":{"date-parts":[[2022,4,7]],"date-time":"2022-04-07T07:38:03Z","timestamp":1649317083000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Molecular Modeling of Subtype-Specific Tat Protein Signatures to Predict Tat-TAR Interactions That May Be Involved in HIV-Associated Neurocognitive Disorders"],"prefix":"10.3389","volume":"13","author":[{"given":"Monray E.","family":"Williams","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben","family":"Cloete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"3974","DOI":"10.1093\/nar\/24.20.3974","article-title":"Structure of HIV-1 TAR RNA in the absence of ligands reveals a novel conformation of the trinucleotide bulge","volume":"24","author":"Aboul-ela","year":"1996","journal-title":"Nucleic Acids Res."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"Gromacs: high performance molecular simulations through multi-level parallelism from laptops to supercomputers","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"W530","DOI":"10.1093\/nar\/gkab294","article-title":"PLIP 2021: expanding the scope of the protein-ligand interaction profiler to DNA and RNA","volume":"49","author":"Adasme","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1371\/journal.pone.0002516","article-title":"Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients","volume":"3","author":"Ancuta","year":"2008","journal-title":"PLoS One"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1212\/01.WNL.0000287431.88658.8b","article-title":"Updated research nosology for HIV-associated neurocognitive disorders","volume":"69","author":"Antinori","year":"2007","journal-title":"Neurology"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"44714","DOI":"10.1074\/jbc.M112.397158","article-title":"Multiple NF-\u03baB sites in HIV-1 subtype C long terminal repeat confer superior magnitude of transcription and thereby the enhanced viral predominance","volume":"287","author":"Bachu","year":"2012","journal-title":"J. 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