How does hemoglobin generate such diverse functionality of physiological relevance

Abstract The absolute values of the O 2 -affinities ( P 50 , K low , and K high ) of hemoglobin (Hb) are regulated neither by changes in the static T-/R-quaternary and associated tertiary structures nor the ligation states. They are pre-determined and regulated by the extrinsic environmental factors such as pH, buffers, and heterotropic effectors. The effect and role of O 2 on Hb are reversibly to drive the structural allosteric equilibrium between the T(deoxy)- and R(oxy)-Hb toward R(oxy)-Hb ( the structural allostery ). R(oxy)-Hb has a higher O 2 -affinity ( K high ) relative to that ( K low ) of the T(deoxy)-Hb ( K high  >  K low ) under any fixed environmental conditions. The apparent O 2 -affinity of Hb is high, as the globin matrix interferes with the dissociation process of O 2 , forcing the dissociated O 2 geminately to re-bind to the heme Fe. This artificially increases [oxy-Hb] and concomitantly decreases [deoxy-Hb], leading to the apparent increases of the O 2 -affinity of Hb. The effector-linked high-frequency thermal fluctuations of the globin matrix act as a gating mechanism to modulate such physical, energetic, and kinetic barriers to enhance the dissociation process of O 2 , resulted in increases in [deoxy-Hb] and concomitant decrease in [oxy-Hb], leading to apparent reductions of the O 2 -affinity of Hb ( the entropic allostery ). The heme in Hb is simply a low-affinity O 2 -trap, the coordination structure of which is not altered by static T-/R-quaternary and associated tertiary structural changes of Hb. Thus, heterotrophic effectors are the signal molecule, which acts as a functional link between these two allosteries and generates the diverse functionality of Hb of physiological relevance. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins.