Amir Bitran : Rare codons coordinate co-translational protein folding to avoid misfolded intermediates
In the cell, many proteins begin folding co-translationally. To ensure proper function, co-translational folding must allow proteins to rapidly reach their native state while avoiding potentially harmful misfolded intermediates. Here we provide evidence that this process may be regulated in vivo by synonymous codon choice. Namely, we hypothesize that rare codons, which are known to be translated more slowly than their synonymous counterparts, may provide time for nascent polypeptide chains to begin folding. Using atomistic Monte Carlo simulations, we investigate the folding of various proteins whose sequences are evolutionarily enriched in rare codons and show that, indeed, these proteins can adopt stable native structure at translational intermediates corresponding to rare codon positions. Moreover, these translational intermediates fold more rapidly than their respective fully synthesized proteins, whose folding is drastically slowed by nonnative interactions. We then predict, using kinetic modeling, that these proteins’ proper co-translational folding relies on rare codons, and that synonymous substitution would dramatically reduce folding efficiency. This work sheds light on the factors that promote proper protein folding in the cellular environment, and on the role of crucial role of kinetics in biological self-assembly more broadly.
- Amir Bitran, William Jacobs, Eugene Shakhnovich -
Harvard University - Biophysics