THAKUR, S.; Mehra, R.

The protein synthesis is an essential target for anti-tubercular drug design. Methionyl-tRNA synthetase (MetRS) typically plays a role in elongation and the initiation of protein synthesis. Molecular recognition of the CAU anticodon of tRNA by MetRS in the two processes is a crucial step. Until now, no known experimental structures for Mycobacterium tuberculosis (Mtb) show this binding. We therefore modeled the Mtb MetRS complexes with initiator and elongator tRNAs to find their differential binding mechanism during molecular dynamics simulations of 6 microseconds. We found that the elongator tRNA binding was stable with the protein, while the initiator tRNA binds transiently, with major intra-tRNA interactions maintained in both. This could be due to fast initiator tRNA charging in contrast to the elongator tRNA, which could take more time to charge. tRNA interacts with the MetRS active site and anticodon domain. The electrostatic attractions between tRNA and the catalytic domain of protein possibly caused its charging with methionine. The repulsive and attractive forces between tRNA and the connective peptide domain and KMSKS loop of protein triggered the opening of the binding pocket, causing the reaction and the product release. At the same time, strong binding of tRNA to the anticodon domain of protein facilitated this reaction. These events show the possible pathway of tRNA charging. tRNA formed salt-bridges with the positively charged Arg and Lys, whereas the negatively charged Asp and Glu caused repulsive binding. In brief, this study provided a plausible mechanism for initiator versus elongator tRNA recognition by Mtb MetRS.