Q.47 Which one of the following amino acid residues will destabilize an α-helix when inserted in the middle of the helix?

(A) Pro     (B) Val     (C) Ile     (D) Leu

Proline destabilizes an α-helix when inserted in its middle due to its unique cyclic structure that disrupts the helix’s hydrogen bonding and backbone flexibility. The correct answer is (A) Pro. Val, Ile, and Leu support helix stability through favorable hydrophobic interactions.

Option Analysis

Proline’s side chain forms a five-membered pyrrolidine ring fused to the backbone nitrogen, restricting φ dihedral angle rotation to about -60° and preventing the N-H group from donating a hydrogen bond essential for α-helix stabilization. This rigid kink breaks the regular 3.6 residues-per-turn pattern, often terminating helices mid-sequence.​

Valine’s branched isopropyl side chain fits well in helix cores, promoting stability via van der Waals packing without backbone disruption. Ileucine’s sec-butyl group similarly favors α-helices through hydrophobic burial, as seen in Chou-Fasman parameters (Pα = 1.08 for Ile, 1.06 for Leu).​

Leucine excels in helices with its isobutyl chain enabling tight packing; it’s among the strongest helix formers alongside Ala and Met.​

The amino acid that destabilizes α-helix when inserted in the middle is proline, a classic helix breaker in protein folding. In competitive exams like CSIR NET or GATE Biotechnology, this MCQ tests understanding of secondary structure constraints.​

Proline’s Helix Disruption Mechanism

Proline’s imino group lacks the H-atom for i to i+4 hydrogen bonding, while its cyclic constraint forces a ~30° bend. Free-energy studies show ΔΔG > 2 kcal/mol destabilization mid-helix.​

Stabilizing Amino Acids: Val, Ile, Leu

• Val (Pα=1.06): β-branched but packs efficiently in coiled coils.

• Ile (Pα=1.08): Similar to Val, prefers helices over sheets.

• Leu (Pα=1.21): Optimal leucine zipper motifs.​

This table highlights proline’s outlier status for quantitative comparison in research contexts.