Which of the following is most unstable condition in protein folding?
(1) Non-polar side chain exposed to outside
(2) Polar side chain present in core of protein
(3) Non polar side chains in core of protein
(4) Polar amino acids exposed to outside

Understanding Stability and Instability in Protein Folding

Protein folding is a highly specific and thermodynamically driven process, where hydrophobic and hydrophilic interactions play a crucial role in determining structural stability. Certain conditions promote stability, while others lead to instability and misfolding.

Correct Answer:

The correct option is (2) Polar side chain present in the core of the protein.

Explanation:

(1) Non-Polar Side Chain Exposed to Outside ❌ (Unstable but not the most unstable)

• Non-polar (hydrophobic) amino acids like Leucine, Valine, Phenylalanine prefer to be buried inside the protein core.
• When exposed on the surface, they interact poorly with water, leading to some instability.
• However, some proteins (membrane proteins) may tolerate this condition.

(2) Polar Side Chain Present in Core of Protein ✅ (Most Unstable)

• Polar amino acids (e.g., Serine, Threonine, Glutamine) prefer to be on the protein surface where they can hydrogen bond with water.
• If trapped inside the hydrophobic core, they cannot form hydrogen bonds with water, leading to energetic instability.
• This results in misfolding, aggregation, or unfolding.

(3) Non-Polar Side Chains in Core of Protein ✅ (Stable Condition)

• Hydrophobic residues are naturally buried in the protein core to avoid water contact.
• This stabilizes the structure by reducing water entropy and increasing van der Waals interactions.

(4) Polar Amino Acids Exposed to Outside ✅ (Stable Condition)

• Polar residues (e.g., Lys, Arg, Asp, Glu) are typically found on the surface, interacting with water.
• This promotes hydrophilic interactions, stabilizing the protein.

Thus, the most unstable condition is (2) Polar side chains buried inside the protein core.

Nearby Topics for Better Understanding

1. Hydrophobic vs. Hydrophilic Interactions in Protein Folding

• Hydrophobic residues form the core to avoid water.
• Hydrophilic residues remain on the surface for interaction.

2. Protein Misfolding and Disease

• Incorrect hydrophilic/hydrophobic distribution can cause diseases like:
  • Alzheimer’s disease (amyloid plaques)
  • Cystic fibrosis (misfolded CFTR protein)
  • Prion diseases (misfolded prion proteins)

3. Thermodynamics of Protein Folding

• ΔG (Gibbs free energy) must be negative for stable folding.
• Burial of hydrophobic residues increases ΔS (entropy of water), promoting folding.
• Incorrect placement of polar residues leads to higher free energy (ΔG > 0), causing unfolding.

Conclusion

The most unstable condition in protein folding occurs when polar side chains are trapped inside the hydrophobic core, as this disrupts hydrogen bonding and increases free energy. Understanding protein stability is essential for structural biology, drug design, and disease research.