# Evidence of evolutionary selection for co-translational folding

## TL;DR

This study provides genome-wide evidence that evolutionary selection favors specific translation rates at certain gene regions to optimize co-translational protein folding, highlighting the importance of kinetics in protein self-assembly.

## Contribution

The paper introduces a statistical method to identify conserved, slowly translated codon regions linked to co-translational folding intermediates across many proteins.

## Key findings

- Regions enriched in slow codons are associated with folding intermediates.
- Domain boundaries explain only a small part of conserved slow codon regions.
- Synonymous substitutions are often selected to optimize translation for folding.

## Abstract

Recent experiments and simulations have demonstrated that proteins can fold on the ribosome. However, the extent and generality of fitness effects resulting from co-translational folding remain open questions. Here we report a genome-wide analysis that uncovers evidence of evolutionary selection for co-translational folding. We describe a robust statistical approach to identify loci within genes that are both significantly enriched in slowly translated codons and evolutionarily conserved. Surprisingly, we find that domain boundaries can explain only a small fraction of these conserved loci. Instead, we propose that regions enriched in slowly translated codons are associated with co-translational folding intermediates, which may be smaller than a single domain. We show that the intermediates predicted by a native-centric model of co-translational folding account for the majority of these loci across more than 500 E. coli proteins. By making a direct connection to protein folding, this analysis provides strong evidence that many synonymous substitutions have been selected to optimize translation rates at specific locations within genes. More generally, our results indicate that kinetics, and not just thermodynamics, can significantly alter the efficiency of self-assembly in a biological context.