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Journal Articles Journal of Molecular Graphics and Modelling Year : 2017

Probing the stereospecificity of tyrosyl- and glutaminyl-tRNA synthetase with molecular dynamics

Abstract

The stereospecificity of aminoacyl-tRNA synthetases helps exclude d-amino acids from protein synthesis and could perhaps be engineered to allow controlled d-amino acylation of tRNA. We use molecular dynamics simulations to probe the stereospecificity of the class I tyrosyl- and glutaminyl-tRNA synthetases (TyrRS, GlnRS), including wildtype enzymes and three point mutants suggested by three different protein design methods. l/d binding free energy differences are obtained by alchemically and reversibly transforming the ligand from L to D in simulations of the protein-ligand complex. The D81Q mutation in Escherichia coli TyrRS is homologous to the D81R mutant shown earlier to have inverted stereospecificity. D81Q is predicted to lead to a rotated ligand backbone and an increased, not a decreased l-Tyr preference. The E36Q mutation in Methanococcus jannaschii TyrRS has a predicted l/d binding free energy difference ΔΔG of just 0.5±0.9kcal/mol, compared to 3.1±0.8kcal/mol for the wildtype enzyme (favoring l-Tyr). The ligand ammonium position is preserved in the d-Tyr complex, while the carboxylate is shifted. Wildtype GlnRS has a similar preference for l-glutaminyl adenylate; the R260Q mutant has an increased preference, even though Arg260 makes a large contribution to the wildtype ΔΔG value.
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hal-01954902 , version 1 (14-12-2018)

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Karen Druart, Maeva Le Guennec, Zoltan Palmai, Thomas Simonson. Probing the stereospecificity of tyrosyl- and glutaminyl-tRNA synthetase with molecular dynamics. Journal of Molecular Graphics and Modelling, 2017, 71, pp.192-199. ⟨10.1016/j.jmgm.2016.11.007⟩. ⟨hal-01954902⟩
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