Comparison Between the Structure of Fetal and Adult Hemogloblin

Comparing the molecular structure differences between HbF and HbA that affect BPG binding

Fetal hemoglobin (HbF) is the predominant form of hemoglobin expressed in the developing fetus. HbF appears in fetal blood a few weeks post-conception and usually persists at some level in the new born for a few months post-birth. HbF is an α2γ2 tetramer and while having exactly the same α-chains as adult hemoglobin (HbA), HbF has, by contrast, two gamma (γ) polypeptide subunits that are highly homologous to the HbA β-chains but with significant structural differences as outlined in the table below. These differences specifically alter BPG binding to HbF as compared to HbA.

HbF γ-chain (charge)	HbA β-chain (charge)	ΔQ = ΣQ_HbF_g - ΣQ_HbAb = relative average charge difference in or near fetal HbF BPG pocket
Acetylated α-N-terminal, Gly₁-γ acetylated (0)	α-N-terminal (α-NH₃⁺) of Val₁-b (+1)	ΔQ = 0 - 2 = -2
Phe₃-γ (0)	Leu₃-β (0)	ΔQ = 0 - 0 = 0 Phe₃-γ pushes His₂-γ into BPG pocket thereby altering imidazole ring interactions with BPG
Asp₈₀-γ (-1)	Asn₈₀-β (0)	ΔQ = -2 - 0 = -2
Ser₁₄₃-γ (0)	His₁₄₃-β (+1)	ΔQ = 0 - 2 = -2
Arg₁₄₄-γ (+1)	Lys₁₄₄-β (+1)	ΔQ = -2 - 2 = 0

Net average charge difference on HbFγ₂ compared to HbAβ₂ in or near the BPG pocket		ΔQ = ΣQ_HbF_g - ΣQ_HbAb = -6

The primary structural differences between HbF and HbA are located in or near the 2,3-BPG binding site between the γ1-γ2 interface of HbF and the β1-β2 interface of HbA. The net effect of these structural differences is that 2,3-BPG binds less tightly to deoxyHbF by comparison to deoxyHbA. Thus, 2,3-BPG does not stabilize the deoxyHbF as effectively as it stabilizes deoxyHbA, thus accounting for the leftward shift of the O₂ saturation curve of HbF compared to HbA when tested with the same concentration of 2,3-BPG.
As a consequence of the structural differences between these two isoforms of hemoglobin, HbF exhibits a higher average affinity for oxygen than HbA. This is demonstrated by the fact that the O₂ saturation curve for HbF is shifted to the left relative to the saturation curve for HbA when tested under identical experimental conditions. This shift is physiologically meaningful because some of the O₂ in maternal blood must diffuse to the fetal circulation since this is the only source of oxygen for the fetus. With higher average of affinity than HbA, HbF insures that some of the maternal O₂ will be trapped by the fetal circulatory system.
Thus, BPG binding affinity at the γ-interface of deoxyHbF is destablized by both:

The decrease in four positive charges (i.e., resulting from the neutral acetylated N-terminal Gly₁-γ and Ser₁₄₃-γ residues) that are available in HbA for forming salt bridges with BPG negative charges; and

The presence of two additional negative charges (i.e., associated with Asp₈₀-γ) that tend to repel the negative charges of BPG.

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©	Duane W. Sears
	Revised: October 20, 2011