Hemoglobin S is the form of hemoglobin found in people with sickle cell disease. Carriers will have both hemoglobin S and another form of hemoglobin (likely hemoglobin A) in their blood cells, while people with sickle cell anemia will only have hemoglobin S.

Hemoglobin A and hemoglobin S vary only in a single point mutation found in the gene for the beta chain. This mutation causes a substitution of the amino acid valine for glutamate in each beta chain.  The difference of the single amino acid causes a change in the binding affinity between hemoglobin molecules. Normally the molecules do not have a strong affinity for each other, but when the valine is substituted for a glutamate, hydrophobic charges of different hemoglobin molecules attract each other and stick together when oxygen concentrations are low (Nelson and Cox 2005).

Hb A and Hb S under conditions of high (above) and low (below) oxygen concentrations. The symptoms of sickle cell are a result of the polymerization of Hb S when oxygen concentrations are low.

This binding of hemoglobin affects the shape of the red blood cell. Hemoglobin polymerizes to form chains that can be as long as 15 microliters when the oxygen concentration is low (Guyton 1991). The bound hemoglobin molecules organize into alpha helices, each helix made up of fourteen chains of hemoglobin molecules (Bridges 2002).These hemoglobin chains often form in deoxygenated cells that have dropped off oxygen in the extremities. When oxygen levels are high and hemoglobin can pick up oxygen, however, the hemoglobin S molecules tend to break away from their chain structure and are more similar to hemoglobin A molecules.

The alpha helix formed by HbS chains under low oxygen conditions. Photo used with permission from Dr. Kenneth Bridges http://sickle.bwh.harvard.edu

As a result of this constant polymerization and depolymerization, the hemoglobin molecules become damaged. The membranes of the red blood cells also become damaged due to cycles of stretching and returning to normal as the cell cycles through the body. A cell can undergo stretching and unstretching (polymerization and depolymerization of hemoglobin) up to four times a minute as it travels through the blood vessels (Bridges 2002). This results in fragile blood cells that are more prone to damage.

When red blood cells undergo too many instances of changes in shape, heme (the iron-containing prosthetic group) may be released from hemoglobin and stick to the membrane of the cell (Bridges 2002). The iron within the heme group causes reactive oxygen species to form; these reactive oxygen species damage the cell membrane, as well as potassium channels found there (Goodman, et al. 1998). These cells will often be destroyed by antibodies, resulting in lower numbers of red blood cells to carry oxygen to tissues (Bridges 2002).