Fetal hemoglobin (HbF, α2γ2) has higher O2 affinity than adult HbA (α2β2) and therefore transfers O2 from maternal to fetal circulation across the placenta. The molecular basis of HbF's higher O2 affinity relates to which specific difference from HbA?

• A γ-chains of HbF bind 2,3-bisphosphoglycerate (2,3-BPG) less avidly than β-chains of HbA, so 2,3-BPG stabilises the T (deoxy) state less effectively in HbF ✓
• B γ-chains have more histidine residues that enhance Bohr effect in HbF
• C HbF has an additional heme group per tetramer that increases cooperative binding
• D α-chains of HbF have higher affinity for O2 due to a different heme pocket geometry

Explanation

2,3-BPG stabilises deoxy-HbA by binding to a positively charged cavity between the two β-chains (primarily to His-143 and Val-1 of β-chains). In HbF, γ-chains replace β-chains. The γ-chain has Ser instead of His at position 143, creating a less electropositive BPG-binding site. Therefore HbF binds 2,3-BPG much less avidly than HbA. Since 2,3-BPG stabilises the low-affinity T state, less 2,3-BPG binding in HbF means it remains more in the high-affinity R state — resulting in a left-shifted oxygen dissociation curve and higher O2 affinity, ensuring net O2 transfer from maternal HbA to fetal HbF across the placenta.

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

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