In SCD the normal adult Hb A is replaced by the mutant sickle Hb S (a2bS2
). For the Hb S mutant, the single amino acid substitution, b6 Glu
to intermolecular Hb S interactions when Hb S is in the deoxygenated
state. It is important to note that conformational changes take place upon O2
loading/unloading, such that the oxygenated ("relaxed"; R) and
deoxygenated ("tense"; T) states of the Hb molecule are distinct.
The structure and identity of amino acid side chains at certain sites in the 8
(designated A-H) of each globin subunit of Hb is fundamental to these O2-dependent
interactions. In the Hb S mutant, the b6 Val of one
in the A-helical fold undergoes a hydrophobic interaction with a
hydrophobic "pocket" region in E-F region of
another bS-globin chain when Hb S is in the deoxygenated
state. A donor-acceptor interaction takes place between two adjacent Hb S
molecules such that the b6 Val, or
interacts with the hydrophobic b85 Leu and b88 Phe residues of the E-F region,
which together form a bS-"acceptor" region.