Re-examining supposed correlations between synonymous codon usage and protein bond angles in E. coli

Abstract A recent paper by Rosenberg et al. [2022] found a surprising correlation between synonymous codon usage and the dihedral bond angles of the resulting amino acid. However, their analysis did not account for the strongest known correlate of codon usage: gene expression. We applied the approach of Rosenberg et al. [2022] to simulated protein-coding sequences that (1) maintain the general relationship between codon usage and gene expression and (2) completely random codon usage. The analysis of the simulated data assuming a general relationship between gene expression and codon usage returned results remarkably similar to the real data. More concerning was the large number of significant results detected when sequences with random codon usage were analyzed. We believe that the specific results of Rosenberg et al. [2022] were confounded by the relationship between codon usage and gene expression, but also that their method is generally prone to detecting noise in protein bond angle distributions.