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Hemoglobin's sigmoidal oxygen binding curve results from cooperative allosteric interactions between its four subunits: when one subunit binds oxygen, it enhances oxygen affinity in the others (T→R state transition), creating a steep binding curve that efficiently loads oxygen in the lungs and releases it in tissues.
Plot the oxygen-hemoglobin dissociation curve and compare to a hyperbolic myoglobin binding curve. Discuss how pH, PCO2, temperature, and 2,3-BPG shift the curve leftward (increased affinity) or rightward (decreased affinity).
From your study of protein quaternary structure, you know that hemoglobin is a tetramer — four polypeptide subunits (two alpha, two beta), each carrying an iron-containing heme group capable of binding one molecule of O2. What makes hemoglobin remarkable is not that it binds oxygen, but *how* the binding of oxygen to one subunit changes the behavior of the others. This phenomenon, cooperativity, produces the characteristic sigmoidal (S-shaped) oxygen-hemoglobin dissociation curve and is the key to hemoglobin's physiological superiority over a simple oxygen carrier.
In its deoxygenated state, hemoglobin exists in the T (tense) state, a conformation held together by salt bridges and hydrogen bonds between subunits that constrain the heme pockets and make oxygen binding difficult. When the first O2 molecule binds to a heme iron, it pulls the iron atom into the plane of the porphyrin ring, tugging the attached histidine residue and triggering a conformational shift in that subunit. This local change propagates through subunit interfaces, breaking stabilizing contacts and progressively shifting the entire tetramer toward the R (relaxed) state, which has much higher oxygen affinity. The result is that the first oxygen is hardest to bind, the second and third are progressively easier, and the fourth binds most readily. On a binding curve, this produces the steep middle section of the sigmoid — a small increase in oxygen partial pressure causes a large jump in saturation.
The physiological payoff of cooperativity becomes clear when you compare hemoglobin to myoglobin, a monomeric oxygen-binding protein in muscle. Myoglobin has a hyperbolic binding curve: it loads oxygen readily at low partial pressures but releases it reluctantly. Hemoglobin's sigmoidal curve means it is nearly fully saturated (~98%) at the high PO2 found in the lungs (~100 mmHg) but releases a large fraction of its oxygen at the lower PO2 of metabolically active tissues (~40 mmHg). The steep portion of the curve falls exactly in the physiological range, making hemoglobin an efficient oxygen delivery system rather than merely a storage molecule.
Several factors fine-tune this delivery by shifting the dissociation curve. The Bohr effect describes how increased H+ concentration (lower pH) and increased PCO2 — both signals of active metabolism — shift the curve rightward, decreasing hemoglobin's oxygen affinity and promoting O2 release precisely where it is needed most. Elevated temperature has the same rightward-shifting effect. 2,3-Bisphosphoglycerate (2,3-BPG), produced by red blood cells during glycolysis, binds in the central cavity of deoxyhemoglobin and stabilizes the T state, further reducing oxygen affinity. At high altitude, 2,3-BPG levels increase as an adaptive response, facilitating oxygen unloading to tissues despite lower arterial PO2. Conversely, fetal hemoglobin (HbF) has gamma subunits that bind 2,3-BPG less tightly, giving it a left-shifted curve and higher oxygen affinity — essential for extracting oxygen from maternal blood across the placenta.