How does Hemoglobin Create Such Diverse Functionality of Physiological Relevance?

Abstract

Hemoglobin (Hb) without heterotropic effectors or stripped Hb, is an O2-carrier with a high-affinity (P50 100 mmHg, KR from 10 to 0.005 /mmHg, KT from 0.3 to 0.005 /mmHg, KR/KT from 1 to >500, and ΔH+ up to −4.4 H+/Hb. Such enhanced functionality of Hb of physiological relevance is accomplished through pH-dependent asymmetric binding of heterotropic effectors to R(oxy)- and T(deoxy)-quaternary structures of Hb, which cause pH-dependent differential modulations/reductions of KR and KT, respectively. No changes in high-resolution static crystallographic T(deoxy)- and R(oxy)-quaternary and tertiary structures of Hb and their heme environment, as well as the axial coordination structures of the deoxy-heme (νFe-His = 215 /cm) and the oxy-heme (νFe-O2 = 567/cm) in solution, are observed, despite KT and KR values are changed as much as 100- and 2,000-folds, respectively. Thus, the assumption that the low-affinity state is caused by the inter-dimeric salt-bridge-linked constraints, the out-of-plane shift of the heme Fe, and the allosteric core constraint in the T(deoxy)-Hb is no longer valid. Although these constraints are completely absent in R(oxy)-Hb, its O2-affinity is modulated as much as 2,000-folds by its interaction with heterotropic effectors. The effector-linked modulation of thermal fluctuation of the protein may be responsible.