Overview of Hemoglobin's Structure/Function Relationships

The special implications of hemoglobin’s unique capacity to bind and transport oxygen in vivo are considered in this chapter. As the oxygen transport protein of the blood, hemoglobin has to the capacity to bind between one and 4 O₂ molecules going from fully desaturated (deoxyHb) to fully saturated hemoglobin (oxyHb). Hemoglobin’s primary function is to bind oxygen diffusing into the bloodstream from the lungs and then to shuttle it to outlying tissues where it is "deposited" primarily for aerobic respiration. Oxygen transport is a highly dynamic process with oxygen being continuously exchanged between the lungs and the capillaries. Because myoglobin (Mb) is the O₂ storage protein of the muscle, hemoglobin in effect also continuously supplies myoglobin O₂ when it becomes depleted of oxygen. sometimes between different forms of hemoglobin in the same individual, such as adult hemoglobin in the maternal blood stream and fetal hemoglobin in the fetal blood stream. The dynamics of these oxygen exchange reactions is regulated or fine-tuned by several metabolically-derived factors that collectively define the oxygen demand of an individual’s physiological state at any given moment.

Among the key metabolic factors regulating the dynamics of hemoglobin’s oxygen exchange reactions is oxygen itself. When oxygen levels are high, the capacity of any one hemoglobin molecule to bind oxygen disproportionately increases with the number of oxygen molecules already bound to it, up to the point of saturation. When environmental oxygen levels are high, partially saturated hemoglobin molecules exhibit enhanced affinity for binding additional oxygen molecules, a specialized behavior referred to as cooperativity or cooperative ligand binding. Equally importantly, hemoglobin also manifests cooperativity in the reverse direction. When environmental oxygen levels are low, hemoglobin’s affinity for oxygen drops disproportionately as fewer and fewer oxygen molecules remain bound to hemoglobin. Thus, there is a cooperative loading or unloading of oxygen from hemoglobin depending on the environmental levels of oxygen.

Cooperative ligand binding is no accident. Rather, it is the remarkable product of the evolutionary molding of hemoglobin’s structure such that it can adopt more than one functional shape or conformation. In this regard, hemoglobin is an allosteric protein with an ability to change shapes, or undego allosteric conformational changes. This property allows hemoglobin to be more responsive to changes in the environmental oxygen levels. As discussed in detail later on, hemoglobin’s cooperative ligand binding behavior can be mathematically approximated by the following Hill equation, named after its discoverer:

Ya, the "saturation fraction" of hemoglobin which is a quanitative measure of hemoglobin’s capacity to bind oxygen. Simply stated, Ya is the average fraction of all available oxygen binding sites in hemoglobin with oxygen actually bound at equilibrium at a specific partial pressure of oxygen, pO₂. For example, when the saturation fraction equals one, each hemoglobin molecule is fully saturated with oxygen molecules bound to all four of the available sites in each molecule. The P₅₀ term in the denominator of this equation is effectively an equilibrium constant unique to hemoglobin. Empirically, P₅₀ equals the equilibrium pO₂ level where hemoglobin molecules are half-saturated, on the average, or 50% saturated with oxygen (Ya = 0.5).

Without the evolutionarily-molded structure of hemoglobin that allows for cooperative oxygen binding, it can easily be shown that hemoglobin’s saturation fraction for oxygen binding would quantitatively obey a different equation, one describing noncooperative ligand binding. Namely,

Although Eqs. (1) and (2) may not appear to be that different, the difference has enormous physiological implications for the individual. As shown later, when the saturation behavior of hemoglobin (i.e., its oxygen binding capacity) is regulated according to the first equation above, each hemoglobin molecule is capable of transporting about twice as many oxygen molecules under normal physiological conditions than would be possible if the saturation behavior obeyed the second equation. Assuming an individual has 5 liters blood volume with about 5 billion red blood cells per milliliter, each containing about 280 million hemoglobin molecules, an individual’s blood is estimated to contain about eight-tens of a kilogram of hemoglobin capable of transporting up to 5 hundreths of a mole of oxygen with each cycle through the lungs. Without hemoglobin’s specialized cooperative ligand binding behavior, nearly twice as much hemoglobin would be needed to transport the same amount of oxygen and this requirement would presumably require twice the blood volume to accommodate a doubling of the number of red blood cells for housing the additional hemoglobin. A doubling of the blood volume and hemoglobin mass would add nearly 12 pounds to an individual’s weight! Clearly, the evolution of hemoglobin’s cooperative oxygen binding behavior serves to economize an individual’s weight and this presumably improves the survivability of the species (as well as the self-esteem of its weight-concious members!). 

Some of the important structural features of hemoglobin are highlighted in the following series of web pages.

Adult Hemoglobin HbA

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© Duane W. Sears
Revised: July 27, 1998