Ab initio HIV-1 Tat-TAR interactions study using hybrid scoring-enhanced molecular modeling across subtypes

Area of Science:

• Molecular Biology
• Virology
• Structural Biology

Background:

• HIV-1 Tat protein is crucial for viral transcription.
• Tat-TAR RNA interactions are key to HIV replication.
• Limited research exists on Tat-TAR interactions across diverse HIV-1 subtypes.

Purpose of the Study:

• To investigate HIV-1 Tat exon 1 and TAR RNA interactions across nine major HIV-1 subtypes.
• To explore how sequence and structural variations influence binding dynamics.
• To introduce a hybrid scoring approach for RNA-protein interaction analysis.

Main Methods:

• Employed a hybrid scoring-enhanced molecular modeling approach.
• Systematically investigated Tat exon 1 from subtypes A, B, C, D, F, G, H, J, and K with TAR RNA.
• Analyzed conserved interaction regions and binding stability.

Main Results:

• Identified a conserved interaction region (residues 48-58) in Tat's Arg-rich basic domain essential for TAR binding.
• Observed consistent core binding mechanisms across subtypes, with variations in binding stability and energetics.
• Subtypes A, B, and D showed strongest binding; subtype B exhibited highest stability. Subtypes G, H, J, and K displayed weaker binding and increased flexibility.
• Substitution of residue R57 decreased binding affinity, confirming experimental findings.

Conclusions:

• Tat-TAR RNA interactions are conserved but influenced by subtype-specific sequence and structural variations.
• Binding affinity and stability differences across subtypes may affect viral transcriptional efficiency.
• The hybrid scoring method provides a robust framework for RNA-protein interaction studies.
• Findings can inform the development of subtype-specific antiviral therapies.