Protein Misfolding
The failure of a polypeptide chain to reach its native three-dimensional structure, often leading to aggregation or degradation.
Protein Misfolding is the failure of a polypeptide to adopt its correct native conformation, resulting in non-functional, aggregation-prone, or degradation-targeted species 1.
How It Works
As a polypeptide exits the ribosome, it navigates an energy landscape toward its thermodynamically stable native fold. Misfolding occurs when kinetic traps, unfavorable co-translational folding rates, or a lack of cognate chaperones cause the chain to adopt incorrect conformations.
In heterologous expression systems, misfolding is common because the host may lack the chaperones, disulfide-bond machinery, or post-translational modifications required by the foreign protein. Rapid translation rates that outpace folding can also drive misfolding, which is why codon optimization must be balanced against translation speed.
Misfolded proteins are either refolded by chaperones, degraded by proteases, or sequestered into inclusion bodies. Each outcome affects product yield and quality differently, making misfolding a central concern in recombinant protein production.
Computational Considerations
AlphaFold and Rosetta predict native structures, while molecular dynamics simulations reveal co-translational folding intermediates. Codon-level translation rate models identify regions where slowing elongation via rare codons could improve folding outcomes, linking sequence design directly to structural quality 2.
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Structure prediction tools like AlphaFold and molecular dynamics simulations identify misfolding-prone regions, informing sequence redesign and expression condition selection.