Cotranslational protein folding through non-native structural intermediates

Area of Science:

• Molecular Biology
• Biophysics
• Computational Biology

Background:

• Protein folding is essential for cellular function, but occurs during translation (cotranslational folding) within the ribosome.
• Misfolding, linked to diseases, arises from disruptions in cotranslational folding pathways.
• Predicting these pathways at an atomistic level remains a significant challenge.

Purpose of the Study:

• To computationally predict and experimentally validate the atomistic details of cotranslational folding pathways.
• To investigate the role of non-native hydrophobic interactions in stabilizing early folding intermediates.
• To understand how the ribosome's environment and molecular chaperones influence cotranslational folding.

Main Methods:

• Atomistic molecular dynamics simulations to predict folding pathways.
• Experimental validation using biophysical techniques.
• Analysis of interactions between nascent peptides and the ribosome exit tunnel.

Main Results:

• A vectorial hierarchy of folding was computationally predicted and experimentally validated.
• Early folding intermediates are stabilized by transient, non-native hydrophobic interactions.
• Disruption of these interactions impairs cotranslational folding.
• The chaperone trigger factor modulates the folding pathway by maintaining peptide dynamics.

Conclusions:

• Surface-exposed residues play a critical, previously unrecognized role in cotranslational folding.
• The findings provide new tools for improving protein folding prediction and protein design.
• This work deepens our understanding of the fundamental mechanisms governing protein biogenesis.