Hemoglobin S (HbS) in deoxygenated state forms fibres due to hydrophobic interaction between the beta-6 valine of one HbS molecule and a hydrophobic pocket on an adjacent HbS molecule. The amino acid that is substituted at beta-6 in normal HbA, and the consequence of this substitution for sickling, is:

• A Glutamate replaced by valine; valine creates a hydrophobic sticky patch absent in HbA ✓
• B Lysine replaced by glutamate; glutamate at beta-6 increases hydrophilicity
• C Glutamine replaced by valine; valine introduces positive charge at beta-6
• D Aspartate replaced by valine; valine reduces negative charge causing aggregation

Explanation

In HbA, beta-chain position 6 is glutamate (negatively charged, hydrophilic). In HbS, a GAG → GTG mutation substitutes valine (hydrophobic, uncharged) at beta-6. When HbS deoxygenates, the T-state conformation exposes a hydrophobic pocket between EF corner beta-85 phe and beta-88 Leu; the beta-6 valine of a neighbouring HbS molecule inserts into this pocket, initiating polymer formation. This is why sickle haemoglobin polymerises only in the deoxy state. HbF (with gamma chains) and HbA2 (delta chains) lack this hydrophobic interaction and inhibit sickling, explaining why high HbF levels ameliorate disease.

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

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