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Aminoacyl-tRNA synthetases (aaRSs) catalyze the activation of the corresponding amino acids and attachment to their cognate tRNAs with extremely high fidelity due to pre- and post-transfer editing processes. We have computationally elucidated a pretransfer editing mechanism in yeast mitochondrial threonyl-tRNA synthetase (MST1) via the combined application of classical molecular dynamics and QM/MM-MD free energy calculations. It is concluded that the pretransfer editing mechanism against seryl-AMP occurs in two steps via an oxyanion intermediate. Importantly, its formation is central to, within the aminoacylation active site, the differential rates at which threonyl-tRNA synthetase (ThrRS) is able to hydrolyze its cognate threonyl-AMP and noncognate seryl-AMP substrates. More specifically, in contrast to that observed when threonyl-AMP is bound in the ThrRS active site, the binding of seryl-AMP enables a …