Calibrating Sickle Cell Disease.

Sickle cell disease is fundamentally a kinetic disorder, in which cells containing the mutated hemoglobin (hemoglobin S; HbS) will cause occlusion if they sickle in the microvasculature, but have minimal (or no) consequences if they sickle in the venous return. Physiologically, sickling always occurs when some ligands are present; nonetheless, the kinetics in the presence of ligands are virtually unstudied. Sickling arises from nucleation-controlled polymer formation, triggered when the HbS loses ligands (e.

Nucleation of sickle hemoglobin mixed with hemoglobin A: experimental and theoretical studies of hybrid-forming mixtures.

Sickle hemoglobin (HbS) is a point mutation of the two β subunits in normal Hb (HbA) that leads to nucleated polymerization and accompanying pathology. We measured the rates of homogeneous and heterogeneous nucleation of HbS in the presence of up to 50% HbA under conditions in which hybrid HbAS molecules will also form. The replacement of 50% of HbS by HbA slows polymerization by factors of ∼100 in the physiological range, which is substantially less than previously thought.

Metastable polymerization of sickle hemoglobin in droplets.

Sickle cell disease arises from a genetic mutation of one amino acid in each of the two hemoglobin beta chains, leading to the polymerization of hemoglobin in the red cell upon deoxygenation, and is characterized by vascular crises and tissue damage due to the obstruction of small vessels by sickled cells. It has been an untested assumption that, in red cells that sickle, the growing polymer mass would consume monomers until the thermodynamically well-described monomer solubility was reached. By photolysing droplets of sickle hemoglobin suspended in oil we find that polymerization does not exhaust the available store of monomers, but stops prematurely, leaving the solutions in a supersaturated, metastable state typically 20% above solubility at 37 degrees C, though the particular values depend on the details of the experiment.