HbS polymerises in the deoxygenated state causing sickle cell disease. At the molecular level, the specific interaction responsible for HbS polymerisation is:

• A Glutamate-6 on beta-chains forms a disulfide bond with adjacent HbS molecules
• B The beta-chain Val6→Glu substitution increases positive charge, promoting ionic interactions between adjacent haemoglobin tetramers
• C Deoxy-HbS undergoes gamma-to-beta chain switch, creating sticky surface residues
• D Valine-6 on beta-chains (replacing glutamate-6) creates a hydrophobic patch that fits into a complementary hydrophobic pocket on adjacent deoxy-HbS molecules ✓

Explanation

The point mutation E6V (Glu→Val at beta-chain position 6) introduces a nonpolar valine in place of the hydrophilic glutamate on the outer surface of the beta-chain. In the deoxy conformation, this creates an exposed hydrophobic 'knob' that fits into a hydrophobic 'socket' (formed by Ala-70 and Phe-85) on a neighbouring deoxy-HbS molecule. This intermolecular contact nucleates linear polymerisation into HbS fibres. In the oxy conformation, the T→R quaternary shift buries this hydrophobic patch, preventing polymerisation — explaining why oxygenation reverses sickling.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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Written and medically reviewed by the StethoPrep medical team.