title: Probing the influence of hypermodified residues within the tRNA3(Lys) anticodon stem loop interacting with the A-loop primer sequence from HIV-1.
abstract: Replication of the HIV-1 virus requires reverse transcription of the viral RNA genome, a process that is specifically initiated by human tRNA3(Lys) packaged within the infectious virion. The primary binding site for the tRNA involves the 3' 18 nucleotides with an additional interaction between an adenine rich loop (A-loop) in the template and the anticodon stem-loop region of the tRNA3(Lys). The loop of the tRNA primer contains two hypermodified base residues and a pseudouridine that are required for a proper binding and activity. Here, we investigate the influence on the structure, dynamics and binding stability of the three modified residues (mnm(5)s(2)U34, t(6)A37 and Ψ39) using extensive molecular dynamics and Quantum Theory of Atoms in Molecules (QTAIM) analysis. Consistent with experiment, the results suggest that the three modified residues are required for faithful binding. Residues mnm(5)s(2)U34 and Ψ39 have a major influence in stabilizing the anticodon loop whereas mnm(5)s(2)U34 and t(6)A37 appear to stabilize the formation of the complex of tRNA3(Lys) with the HIV-1 A-loop.
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, United States.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Galindo-Murillo
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, United States.
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Davis
authors.affiliation: Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT 84112, United States. Electronic address: tec3@utah.edu.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Cheatham
mesh_terms: D000926:Anticodon; D017931:DNA Primers / Q000737:chemistry*; D004583:Electrons; D015497:HIV-1 / Q000235:genetics*; D012357:RNA, Transfer, Lys / Q000737:chemistry*
chemical_list: D000926:Anticodon; D017931:DNA Primers; D012357:RNA, Transfer, Lys
keywords: Anti-codon loop; HIV genome; HIV transcription; Molecular dynamics; QTAIM; Quantum mechanics; RNA dynamics; tRNA