Cotranslational folding allows misfolding-prone proteins to circumvent deep kinetic traps

Amir Bitran, William M. Jacobs, Xiadi Zhai, Eugene Shakhnovich

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


Many large proteins suffer from slow or inefficient folding in vitro. It has long been known that this problem can be alleviated in vivo if proteins start folding cotranslationally. However, the molecular mechanisms underlying this improvement have not been well established. To address this question, we use an all-atom simulation-based algorithm to compute the folding properties of various large protein domains as a function of nascent chain length. We find that for certain proteins, there exists a narrow window of lengths that confers both thermodynamic stability and fast folding kinetics. Beyond these lengths, folding is drastically slowed by nonnative interactions involving C-terminal residues. Thus, cotranslational folding is predicted to be beneficial because it allows proteins to take advantage of this optimal window of lengths and thus avoid kinetic traps. Interestingly, many of these proteins' sequences contain conserved rare codons that may slow down synthesis at this optimal window, suggesting that synthesis rates may be evolutionarily tuned to optimize folding. Using kinetic modeling, we show that under certain conditions, such a slowdown indeed improves cotranslational folding efficiency by giving these nascent chains more time to fold. In contrast, other proteins are predicted not to benefit from cotranslational folding due to a lack of significant nonnative interactions, and indeed these proteins' sequences lack conserved C-terminal rare codons. Together, these results shed light on the factors that promote proper protein folding in the cell and how biomolecular self-assembly may be optimized evolutionarily.

Original languageEnglish (US)
Pages (from-to)1485-1495
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - Jan 21 2020

All Science Journal Classification (ASJC) codes

  • General


  • Codon usage
  • Cotranslational folding
  • Evolution
  • Self-assembly
  • protein folding


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