In hemoglobin S (HbS), glutamate at position 6 of the beta-chain is replaced by valine. During deoxygenation, HbS polymerizes. Which structural feature of the deoxy conformation DRIVES this polymerization?

• A The valine substitution creates a hydrophilic patch that attracts water molecules, promoting aggregation
• B HbS polymerizes only in the oxy conformation when valine is exposed
• C Deoxy-HbS exposes a hydrophobic valine residue that fits into a complementary hydrophobic pocket on an adjacent deoxy-HbS molecule, nucleating polymer formation ✓
• D The sickle mutation reduces negative charge on the beta-chain surface, allowing electrostatic attraction between molecules

Explanation

Glutamate-6 is hydrophilic and negatively charged; its replacement with valine creates a hydrophobic 'sticky patch' on the beta-chain exterior. In the deoxy-T (tense) conformation, conformational changes open a hydrophobic acceptor pocket on adjacent beta-chains (involving Phe-85 and Leu-88). The exposed valine-6 inserts into this pocket on a neighboring deoxy-HbS, initiating the nucleation that leads to fiber formation. The oxy-R (relaxed) conformation does not expose the complementary pocket, explaining why sickling occurs on deoxygenation. Polymer formation follows a delay period — this is the basis for therapeutic approaches increasing HbF or using oxygen.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.