Pathway regulation mechanism by cotranslational protein folding

Area of Science:

• Biophysics
• Computational Biology
• Molecular Biology

Background:

• Discrepancies exist between in vivo cotranslational protein folding and in vitro free folding.
• Microscopic mechanisms driving these folding differences are not well understood.

Purpose of the Study:

• To investigate the mechanistic differences between cotranslational and free protein folding.
• To reconcile conflicting experimental observations regarding in vivo and in vitro protein folding.

Main Methods:

• Developed a general protein cotranslational folding (GPCTF) simulations framework.
• Modeled the ribosomal exit tunnel and translation process.
• Performed extensive molecular dynamics simulations (over 8 ms) on three proteins.

Main Results:

• Cotranslational folding yields a nascent peptide with higher helix content and fewer nonnative interactions upon ribosomal exit.
• Subsequent folding pathways mirror free folding but exhibit altered ratios.
• Translation speed acts as a key modulator of these folding pathway ratios.

Conclusions:

• The study elucidates the pathway regulation mechanism intrinsic to cotranslational folding.
• Findings reconcile discrepancies in existing experimental data on protein folding.
• Provides significant insights into the in vivo protein folding process.