Protein Folding, Shape & Function

How do proteins fold into their functional shapes?

Protein folding is driven by chemical interactions among amino acid side chains (R groups) after the polypeptide is synthesized.
The process moves from a linear chain to a stable three-dimensional conformation (native structure).

The Main Stages?

1. Primary structure – amino acid sequence.

2. Secondary structure – local α-helices and β-sheets formed by backbone hydrogen bonds.

3. Tertiary structure – overall 3-D folding driven by R-group interactions (ionic, hydrophobic, hydrogen, disulfide).

4. Quaternary structure – multiple polypeptide subunits assemble into one functional complex.

Forces guiding folding?

• Hydrophobic effect: non-polar residues bury inside; polar residues remain outside.

• Hydrogen bonds: stabilize helices and sheets.

• Disulfide bonds: covalent S–S links lock regions in place (e.g., in insulin).

• Ionic interactions: between charged side chains (acidic/basic).

• Van der Waals forces: stabilize close packing of atoms.

What determines a protein’s final shape, and why is shape critical for function?

The primary amino acid sequence completely determines the final folded shape because it dictates where bonds and interactions can form.
Shape dictates function — only the correct 3-D conformation creates:

• Enzyme active sites with precise geometry for substrate binding.

• Receptor binding pockets for hormones or neurotransmitters.

• Transport channels in membranes with correct pore orientation.

Even a single amino acid substitution can distort shape enough to inactivate the protein (example: sickle cell anaemia).

What are molecular chaperones, and how do they assist in protein folding?

Molecular chaperones are specialized helper proteins that assist newly synthesized polypeptides to fold correctly.
They:

• Prevent aggregation of unfolded chains.

• Provide a protected environment for folding.

• Use ATP hydrolysis to bind and release polypeptides in cycles until correct folding is achieved.

Examples: Hsp70, chaperonins (GroEL/GroES).

Without chaperones, many proteins would misfold or form non-functional aggregates.

What happens if a protein misfolds, and what diseases are linked to misfolded proteins?

Misfolded proteins often lose their function and may aggregate, disrupting cellular processes.
Examples of diseases caused by misfolded proteins:

• Alzheimer’s disease: β-amyloid peptide aggregation.

• Parkinson’s disease: α-synuclein aggregation.

• Prion diseases: infectious misfolded prion proteins cause others to misfold (e.g., Creutzfeldt–Jakob disease).

Cells attempt to remove misfolded proteins using proteasomes and autophagy, but if these fail, toxicity results.

How can environmental conditions affect protein shape (denaturation)?

Extreme temperature, pH, or chemical agents can disrupt non-covalent bonds maintaining tertiary and quaternary structure.
This process is called denaturation — the protein unfolds and loses its specific 3-D shape, and therefore its biological activity.

Examples:

• High temperature breaks hydrogen and hydrophobic bonds → loss of shape (e.g., egg white coagulation).

• pH extremes alter charge on R groups → disrupt ionic bonds.

• Heavy metals (Hg²⁺, Pb²⁺) bind sulfhydryl groups and disrupt structure.

Denaturation is usually irreversible, though mild cases may allow renaturation when conditions return to normal.