A key step in protein synthesis is acceptance of the aa-tRNA complex into the A-site of the ribosomal decoding center. Correct codon:anticodon matching ensures proper translation of the mRNA sequence into a functional protein. An incorrect match can result in production of peptide fragments, mistranslation and therefore non-functioning proteins, or stalling of the translation process. Alkylation damage in the form of O6-methylguanine at the 1st or 3rd position in the codon has been shown to promote acceptance of near-cognate matches (i.e. mistranslation); however, damage at the 2nd position results in ribosomal stalling. On the other hand, oxidation damage (e.g. 8-oxoguanine) stalls translocation regardless of its position in the mRNA codon. It has been proposed that the alkylation damage at the 2nd position induces conformational changes that are influential in the stalling behavior. Unfortunately, the available in vitro and in vivo studies do not provide sufficient mechanistic detail to support this hypothesis or to fully explain the observed selectivity. In contrast, in silico studies can provide significant insight into changes in the conformation of the decoding center when damaged mRNA is present. In this light, we report an all-atom MD study of the effects of alkylation damage to codon positions 1, 2 or 3 within the A-site of the prokaryotic ribosomal decoding center in the presence of a cognate or near-cognate aa-tRNA anticodon. We thereby reveal important information about the role of conformational changes in the decoding center in dictating the outcomes of the translation of damaged mRNA.

Influence of damaged mRNA on codon:anticodon selectivity in the ribosomal decoding center

251st National Meeting (2016)

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