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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 = ΣQHbFg - ΣQHbAb
 = relative average charge difference
in or near fetal HbF BPG pocket
Acetylated α-N-terminal,
Gly1 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
Phe3pushes 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 (+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 = ΣQHbFg - ΣQHbAb = -6
  1. 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
  2. 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