4.5 Mechanisms of Protein Folding

How proteins fold to achieve a stable state is still an active area of research.

Levinthal’s paradox states that proteins cannot fold by sampling all possible conformations - this would take 1030 years or more!

Hence, proteins must be able to fold via a limited amount of “folding pathways.”

4.5.1 Generalizations

It is believed that secondary structures (especially \(\alpha\)-helices) form first; nonpolar residues initially cluster in a process called hydrophobic collapse.

Later steps in the folding process involve the formation of long-range interactions between distant secondary structures and other elements. This folding process may also involve one or more intermediates termed molten globules (i.e., a hydrophobic collapse has occured, albeit the protein is only partially folded).

Helix Formation and Collapse

Figure 4.14: Helix Formation and Collapse

The protein folding process can be thought of as a funnel of free energies. The topmost portion of figure 4.14 represents many possible unfolded states.

As a protein folds, its polypeptide chain moves down the funnel to lower net free energies, but also lower conformational entropies (i.e., lower \(S_{pro}\)).

4.5.2 Protein misfolding

If proteins do not fold properly, then not only does it result in a waste of energy and resources, but also poses a potential threat to the organism (e.g., the formation of \(\beta\)-amyloid plaques in Alzheimer’s disease).

Diseases Associated with Amyloid Formation

Figure 4.15: Diseases Associated with Amyloid Formation

Figure 4.15 displays a list of diseases that are associated with amyloids - a class of protein diseases associated with protein misfolding. These amyloid formations can be toxic to the cell or the organism and form via intermolecular interactions of unfolded or partially folded polypeptides.

Molecular Chaperones

Figure 4.16: Molecular Chaperones

Hence, in order to prevent the above from happening, cells have a number of molecular chaperones to catalyze protein folding and inhibit the formation of misfolded proteins. These include the following from figure 4.16:

  1. Hsp70 and Hsp40 chaperones
  2. Chaperonin chaperone proteins
  3. Protein disulfide isomerase (which catalyzes disulfide bond interchanging)
  4. Peptide prolyl cis-trans isomerase (which catalyzes Pro cis-trans conversion)