Probing the structure of human tRNA(3)(Lys) in the presence of ligands using docking, MD simulations and MSM analysis

The tRNA(3)(Lys), which acts as a primer for human immunodeficiency virus type 1 (HIV-1) reverse transcription, undergoes structural changes required for the formation of a primer–template complex. Small molecules have been targeted against tRNA(3)(Lys) to inhibit the primer–template complex formation. The present study aims to understand the kinetics of the conformational landscape spanned by tRNA(3)(Lys) in apo form using molecular dynamics simulations and Markov state modeling. The study is taken further to investigate the effect of small molecules like 1,4T and 1,5T on structural conformations and kinetics of tRNA(3)(Lys), and comparative analysis is presented. Markov state modeling of tRNA(3)(Lys) apo resulted in three metastable states where the conformations have shown the non-canonical structures of the anticodon loop. Based on analyses of ligand–tRNA(3)(Lys) interactions, crucial ion and water mediated H-bonds and free energy calculations, it was observed that the 1,4-triazole more strongly binds to the tRNA(3)(Lys) compared to 1,5-triazole. However, the MSM analysis suggest that the 1,5-triazole binding to tRNA(3)(Lys) has brought rigidity not only in the binding pocket (TΨC arm, D–TΨC loop) but also in the whole structure of tRNA(3)(Lys). This may affect the easy opening of primer tRNA(3)(Lys) required for HIV-1 reverse transcription.