Abstract
Recent experiments and simulations have demonstrated that proteins can fold on the ribosome, but the importance of co-translational folding for the fitness of an organism remains an open question. 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 conserved loci within genes that are significantly enriched in slowly translated codons. 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.