Comparing these distributions for pairs of synonymous codons, statistically significant differences are observed. To probe for such a direct and local association, we developed a method for estimating and comparing codon-specific backbone dihedral angle distributions, which we term codon-specific Ramachandran plots. To the best of our knowledge, no studies have investigated whether the specific backbone torsion of an amino acid is associated with the synonymous codon from which it was translated. Together this suggests that we are far from fully understanding the role of codon usage in orchestrating protein folding. Nevertheless, whether and how synonymous variants of a gene will alter the conformation of the final folded protein is still poorly predictable and additionally the literature is riddled with reports of single synonymous mutations causing measurable functional effects that are not well-explained by current mechanisms 21, 22, 23, 24. This mechanism provides an indirect association between codon usage and global protein structure. Translation rate is affected by synonymous codon usage which alters mRNA structure and tRNA abundance, the latter coevolving with codon bias 15, 16, 17, 18, 19, 20. Numerous studies have shown that changes in the rhythm of translation can alter the kinetics of co-translational folding and so, the global conformation of the final protein product 13, 14. Changes in synonymous coding can alter mRNA splicing, mRNA folding, and stability 6, 7, 8, and can affect translational speed and accuracy and the conformation of the translated protein 9, 10, 11, 12. Once considered a silent redundancy of the genetic code, synonymous coding is now known to be functionally important, subject to evolutionary selective pressure and clearly associated with disease 1, 2, 3, 4, 5. 61 codons map to 20 amino acids, meaning that most amino acids are encoded by more than one, synonymous, codon. Transfer RNA (tRNA) molecules recognize codons of the messenger RNA (mRNA) sequence as it passes through the ribosome and deliver specific amino acids sequentially for addition to the growing peptide chain.
One of the most critical cellular processes is the decoding of genetic information into functional proteins. Finally, we urge for the inclusion of exact genetic information into structural databases. Although these findings cannot pinpoint the causal direction of this dependence, we discuss the vast biological implications should coding be shown to directly shape protein conformation and demonstrate the usefulness of this method as a tool for probing associations between codon usage and protein structure. This shows that there exists a dependence between codon identity and backbone torsion of the translated amino acid. Here we develop a method for computing and comparing codon-specific Ramachandran plots and demonstrate that the backbone dihedral angle distributions of some synonymous codons are distinguishable with statistical significance for some secondary structures.
Once considered inconsequential to the formation of the protein product, there is evidence to suggest that codon usage affects co-translational protein folding and the final structure of the expressed protein. Synonymous codons translate into chemically identical amino acids.
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