'de novo' post-translational protein folding

Definition

Target type: biologicalprocess

The process of assisting in the correct noncovalent folding of newly formed polypeptides or folding intermediates of polypeptides that have exited the ribosome and/or have been stabilized and transferred by other chaperone proteins. This process could involve several cycles of ATP hydrolysis. [GOC:rb]

De novo protein folding is a fundamental biological process that involves the spontaneous acquisition of a functional three-dimensional structure by a polypeptide chain. This process occurs after translation and is essential for protein function. Here's a detailed breakdown:

1. **Unfolding:** Newly synthesized polypeptide chains emerge from ribosomes in an extended, unstructured state. This initial state is often referred to as a "random coil," lacking a defined three-dimensional structure.

2. **Initial Interactions:** As the polypeptide chain emerges, weak non-covalent interactions begin to form between amino acid residues. These interactions include hydrogen bonds, hydrophobic interactions, electrostatic interactions, and van der Waals forces.

3. **Folding Pathway:** The polypeptide chain explores a vast conformational space, sampling various conformations through random fluctuations. These fluctuations are driven by thermal energy and influenced by the interactions between amino acid residues. The folding process is not a linear pathway, but rather a complex landscape with multiple possible routes.

4. **Folding Nucleus:** Specific amino acid sequences within the polypeptide chain may have a higher propensity to interact, forming stable, local structures known as folding nuclei. These nuclei act as starting points for the folding process.

5. **Folding Intermediate:** As the folding nucleus forms, the polypeptide chain begins to fold around it, creating a partially folded intermediate. These intermediates may be metastable, meaning they are relatively stable but not yet fully folded.

6. **Chaperones:** Cellular chaperone proteins play a critical role in assisting the folding process. They prevent misfolding and aggregation by binding to partially folded polypeptide chains, providing a controlled environment for folding.

7. **Final Structure:** Through a series of conformational changes and interactions, the polypeptide chain eventually reaches its final, native three-dimensional structure. The native state is characterized by a specific arrangement of amino acid residues, creating a functional protein with a defined shape.

8. **Folding Stability:** The final structure is thermodynamically stable, meaning it represents the lowest energy state for the polypeptide chain. This stability is maintained by the balance of non-covalent interactions and the formation of a compact, functional structure.

9. **Misfolding and Aggregation:** Sometimes, polypeptide chains can misfold, leading to the formation of non-functional aggregates. These aggregates can be harmful to cells, contributing to diseases like Alzheimer's and Parkinson's.

In summary, de novo protein folding is a complex and highly regulated process that involves a series of interactions, conformational changes, and the assistance of chaperone proteins. The process is essential for the production of functional proteins, which are critical for all cellular processes.
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