Using molecular dynamics to map interaction networks in an aminoacyl‐tRNA synthetase

Long‐range functional communication is a hallmark of many enzymes that display allostery, or action‐at‐a‐distance. Many aminoacyl‐tRNA synthetases can be considered allosteric, in that their trinucleotide anticodons bind the enzyme at a site removed from their catalytic domains. Such is the case with E. coli methionyl‐tRNA synthase (MetRS), which recognizes its cognate anticodon using a conserved tryptophan residue 50 Å away from the site of tRNA aminoacylation. The lack of details regarding how MetRS and tRNA Met interact has limited efforts to deconvolute the long‐range communication that occurs in this system. We have used molecular dynamics simulations to evaluate the mobility of wild‐type MetRS and a Trp‐461 variant shown previously by experiment to be deficient in tRNA aminoacylation. The simulations reveal that MetRS has significant mobility, particularly at structural motifs known to be involved in catalysis. Correlated motions are observed between residues in distant structural motifs, including the active site, zinc binding motif, and anticodon binding domain. Both mobility and correlated motions decrease significantly but not uniformly upon substitution at Trp‐461. Mobility of some residues is essentially abolished upon removal of Trp‐461, despite being tens of Ångstroms away from the site of mutation and solvent exposed. This conserved residue does not simply participate in anticodon binding, as demonstrated experimentally, but appears to mediate the protein's distribution of structural ensembles. Finally, simulations of MetRS indicate that the ligand‐free protein samples conformations similar to those observed in crystal structures with substrates and substrate analogs bound. Thus, there are low energetic barriers for MetRS to achieve the substrate‐bound conformations previously determined by structural methods. Proteins 2007. © 2007 Wiley‐Liss, Inc.