Haemoglobin S (HbS) in sickle cell disease polymerises in the deoxy state because:

• A The Val6 residue creates a hydrophobic complementary binding site (EF pocket) on the surface of adjacent deoxyHbS beta-chains enabling fibre nucleation ✓
• B The Glu6Val mutation exposes a hydrophilic patch on the beta-globin surface that forms hydrogen bonds with adjacent molecules
• C Sickling occurs because HbS has reduced oxygen affinity making it permanently deoxygenated
• D The Val6 mutation destabilises the alpha1-beta2 interface causing quaternary T-state locking

Explanation

The beta-globin Glu6Val substitution in HbS replaces a negatively charged hydrophilic glutamate with a non-polar valine residue. In the deoxy (T-state) conformation of HbS, this mutant Val6 protrudes from a hydrophobic 'sticky patch' on the beta-chain surface and specifically inserts into a complementary hydrophobic EF pocket (between Ala70 and Phe85) on the beta-chain of an adjacent deoxyHbS molecule. This Val6-EF pocket interaction drives fibre nucleation and propagation. OxyHbS (R-state) undergoes conformational change that occludes the EF pocket, preventing polymerisation—explaining why sickling is oxygen tension-dependent. HbS has normal oxygen affinity; sickling is a structural polymerisation phenomenon, not a consequence of low O2 affinity per se.

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

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