Interplay of Conformational Plasticity and Substrate Polymorphism in Malarial tyrosyl-tRNA Synthetase

Abstract

Aminoacyl-tRNA catalyze ATP dependent attachment of amino-acids to their cognate tRNAs. Malarial tyrosyl-tRNA synthetase, a validated drug target, exhibits an intricate conformational landscape for the evolutionarily conserved ATP-binding loop. To examine the conformational dynamics, all-atom model for homodimeric holo- tyrosyl-tRNA synthetase was simulated for half microsecond under isochoric-isothermal conditions using AMBER force-fields. Root-mean-square deviation (RMSD), with respect to the crystal structure, for one of the monomers was ∼2Å while for the other monomer it reached upto a maximum of ∼3.5Å. The two monomers also showed markedly different atomic fluctuations during the simulation. In one monomer, loop regions in the N- and C-terminal domains had much higher calculated B-factors compared to the corresponding secondary structure elements in the other monomer. Intriguingly, the monomer with lower overall RMSD had higher atomic fluctuations than the monomer having greater conformational changes. The bound tyrosyl-adenylate sampled discrete conformational sub-states as evident by the distribution of adenosyl dihedral angles. The change in ligand conformation was triggered after 300ns; concomitant with the increased RMSD for the protein. The alpha torsion angle for both the ligands fluctuated between 45° to 90°, however, during 300 to 400ns, for one of the ligands, these angles were in 290° to 340° range. Further, for the same ligand, pairwise distribution for the beta and chi torsions showed presence of three distinct conformations. Interplay between protein and ligand dynamics has also been analyzed by monitoring ligand hydration pattern and variation in the intermolecular interactions. These results insightfully capture the distinct conformational states for the ATP binding loops and guide to dissect the ligand stabilizing interactions within the active site. The observed intermolecular dynamics would prove valuable in astutely designing experiments to discover potential leads against malaria.