The assembly process in HIV-1 has become a new target for infected HIV-1 patient treatment. During this process, the viral genomic RNA and precursor protein are assembled at the permeable membrane and tRNA(Lys3) is packed into a new virion as the primer for the reverse transcription process. The packaging of tRNA(Lys3) arises from the interaction of HIV-1 Gag and hLysRS. To better understand the formation of this ternary complex, the interaction study of LysRS-peptide complex using a combination of circular dichroism, molecular dockings and molecular dynamic simulations are reported here. The circular dichroism experiments confirm that the sh-H4 peptide, containing 10 amino acid residues from helix4 of C-terminal domain of HIV-1 capsid protein (CA-CTD), can be induced to form a helical structure upon binding to hLysRS. Molecular docking analysis of LysRS (hLysRS and eLysRS) with the sh-H4 peptide revealed the two possible arrangements of the peptide upon the binding event. Molecular dynamics based free energy calculations of the peptide binding process are used to determine the interactions as well as the important amino acid residues involving in binding. The peptide is found to lie against helix 7 of LysRS in a perpendicular fashion. Additionally, the peptide preferably interacts with hLysRS over eLysRS including strong hydrogen bond interactions between R247-Q219 and R241-E212. Interestingly, these amino acid residues are found in both LysRS and CA-CTD. These important residues appear to be a vital feature of the LysRS-CA-CTD complex and may ultimately lead to the inhibitor design to block the Gag-LysRS interaction.
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