Human immunodeficiency virus type 1 (HIV-1) requires the human tRNA(3)(Lys) as a reverse transcriptase (RT) primer. The annealing of 3' terminal 18 nucleotides of tRNA(3)(Lys) with the primer binding site (PBS) of viral RNA (vRNA) is crucial for reverse transcription. Additional contacts between the A rich (A-loop) region of vRNA and the anticodon domain of tRNA(3)(Lys) are necessary, which show the specific requirement of tRNA(3)(Lys). The importance of modified nucleosides, present in tRNA(3)(Lys), in giving stability to the primer-template complex has been determined in earlier experiments. It has been observed that the PNA oligomer targeted to PBS of vRNA destabilized the crucial interactions between primer and template due to which the reverse transcription is inhibited. Molecular dynamics simulations have been carried out to study the effect of modified nucleosides on the vRNA-tRNA(3)(Lys) complex stability and the destabilization effect of PNA oligomer on the vRNA-tRNA(3)(Lys)-PNA complex. The root-mean-square deviation, hydrogen bonding, tertiary interactions, and free energy calculations of the simulation data support the experimental results. The analyses have revealed the structural changes in PBS region of vRNA which might be another strong reason for the inability of RT binding to 7F helix for its normal functioning of reverse transcription.
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