Haemoglobin S (HbS) polymerises when deoxygenated because valine replaces glutamate at position 6 of the beta chain. Which physical property of the Val-for-Glu substitution directly drives sickling?

• A Valine is smaller than glutamate, reducing steric hindrance and allowing tighter packing of Hb tetramers
• B Glutamate-6 normally participates in haem attachment; its loss destabilises haem and promotes polymerisation
• C Valine increases the isoelectric point of HbS so it precipitates at physiological pH
• D Loss of negative charge removes electrostatic repulsion between Hb molecules, but the critical change is that valine creates a hydrophobic patch that fits into a complementary hydrophobic pocket on the adjacent deoxyHbS beta chain ✓

Explanation

In deoxyHbS, the hydrophobic valine-6 of the beta chain protrudes from the surface and inserts into a complementary hydrophobic acceptor pocket formed by phenylalanine-85 and leucine-88 of the beta chain on the adjacent Hb tetramer, driving lateral and linear polymerisation into the 14-stranded rope-like fibres that distort the RBC membrane. In oxyHbS, conformational changes in the T→R state transition obscure this hydrophobic contact site, explaining why HbS does not polymerise when oxygenated. The loss of negative charge (Glu→Val) is required (HbC has Lys at β6 but polymerises less), but the primary driver is the hydrophobic interaction, not electrostatic changes per se.

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

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