Protein folding

Protein folding is the process by which a linear polypeptide chain, synthesized from a sequence of amino acids, acquires its functional three-dimensional structure. This structural conformation is essential for the protein's biological activity and is determined primarily by the sequence of amino acids in the polypeptide. The correct folding is crucial as misfolded proteins can lead to loss of function or diseases, such as neurodegenerative disorders associated with amyloid fibrils and prions.

Figure 1: Protein Folding. (Public Domain; Dr. Kjaergaard via Wikipedia)

Mechanism of Protein Folding

The mechanism of protein folding involves several key interactions and stages:

Primary Structure: The sequence of amino acids (the primary structure) dictates how the protein will fold. Each amino acid has unique side chains (R-groups) that influence interactions during folding

Secondary Structure Formation: As the polypeptide chain begins to fold, it forms secondary structures such as alpha-helices and beta-sheets through hydrogen bonding between backbone atoms. These structures contribute to the overall stability and shape of the protein

Tertiary Structure Development: The secondary structures further fold into a three-dimensional shape known as the tertiary structure. This is stabilized by various interactions, including:

Hydrophobic Interactions: Non-polar side chains tend to cluster away from water, driving the folding process.

Hydrogen Bonds: These bonds form between polar side chains and contribute to stability.

Ionic Interactions: Attraction between charged side chains helps maintain structure.

Disulfide Bridges: Covalent bonds between cysteine residues can provide additional stability to the folded protein

Role of Chaperones: In vivo, protein folding is often assisted by molecular chaperones, which help prevent misfolding and aggregation by stabilizing unfolded or partially folded intermediates. For example, Hsp70 chaperones bind to nascent polypeptides during synthesis, while Hsp60 chaperonins provide an isolated environment for proper folding

Folding Pathways: The process typically follows a funnel-like energy landscape where proteins transition from high-energy unfolded states to lower-energy folded states. This pathway includes a fast initial stage leading to a molten globule state followed by a slower transition to the native state

Quality Control Mechanisms: Cells employ various quality control mechanisms to ensure proper protein folding, including proteasomes for degrading misfolded proteins and autophagy pathways for recycling damaged proteins