Allosteric Mechanism of Oxygen-Binding in Hemoglobin

The widely held structure-based mechanism of cooperative oxygen-binding in hemoglobin (Hb), in which the oxygen-affinity of Hb is regulated by the T to R-quaternary and associated tertiary structural transition, is based upon the assumption of the structure-function correlation: ([deoxy-state] =[T-quaternary structure]=[low-affinity state]) and ([oxy-state]=[R-quaternary structure]= [high-affinity state]. Simultaneous measurements of the quaternary structure by proton NMR and the oxygen-affinity by oxygen-binding equilibrium have yielded the following structural/functional states of Hb: (IV) T(deoxy)Hb with extreme low-affinity, (V) R(oxy)Hb with extreme low-affinity, and (VI) T(oxy)Hb with extreme low-affinity in the presence of potent heterotropic effectors as well as more conventional (II) T(deoxy)Hb with low-affinity and (III) R(oxy)Hb with high-affinity in the absence of heterotropic effectors. These results indicate the above-mentioned assumed structure-function correlation is no longer valid. The structure-based allosteric mechanism of Hb describes merely ligation-linked structural allostery rather than the cooperative mechanism of Hb. The structure and the function ( the oxygen-affinity, the cooperativty, and the Bohr effect) of Hb are regulated independently by a tug of war between the allosteric effects of oxygen (T-->R and increasing affinity) and the opposing allosteric effects of heterotropic effectors (T<--R and decreasing affinity) rather than the T to R-quaternary and associated tertiary structural transition. The oxygen-affinity is regulated by effector-linked dynamic structural changes.