Cotranslational Protein Folding Through Non-Native Structural Intermediates

Area of Science:

• Molecular Biology
• Biophysics
• Computational Biology

Background:

• Cotranslational protein folding is crucial for cellular function.
• Misfolding due to altered translation dynamics is linked to diseases.
• Predicting these folding pathways remains a significant challenge.

Purpose of the Study:

• To computationally predict and experimentally validate the vectorial hierarchy of cotranslational protein folding.
• To investigate the role of non-native hydrophobic interactions in stabilizing early folding intermediates.
• To understand how the chaperone Trigger Factor influences cotranslational folding.

Main Methods:

• Atomistic-level computational prediction of folding pathways.
• Experimental validation of predicted folding intermediates and interactions.
• Analysis of the impact of disrupting hydrophobic interactions on folding.
• Investigating the effect of Trigger Factor on nascent peptide dynamics.

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 destabilizes intermediates and impairs protein folding.
• The chaperone Trigger Factor modulates the folding pathway by maintaining peptide dynamics.

Conclusions:

• Surface-exposed residues play a critical role in protein folding on the ribosome.
• The findings provide insights into the fundamental mechanisms of cotranslational folding.
• Developed tools can improve the prediction of protein folding and aid in protein design.