Fig 3. Homology model of cinnamon teal HbA showing the location of a single α-chain amino acid replacement (α^A9Asn→Ser) that distinguishes high- and low-altitude variants.

Replacement of the ancestral Asn with Ser at α^A9 eliminates an intrasubunit hydrogen bond (shown in magenta) between the δ2-nitrogen of α^A9Asn and the γ-oxygen of α^A124Ser in deoxyHb. The loss of this noncovalent bond is predicted to destabilize the low-affinity T-state quaternary structure, thereby shifting the allosteric equilibrium in favor of the high-affinity R-state.