Nanoscale insights suggest means to suppress the primary pathogenic event of sickle cell anemia
V.V. Uzunova, W. Pan, O. Galkin, P.G. Vekilov
University of Houston, US
Keywords: sickle cell anemia, nucleation, polymerization, intermolecular interactions
Abstract:The polymerization of sickle cell hemoglobin (HbS) is the primary event in the pathophysiology of sickle cell anemia. Polymerization starts with nucleation, whereby nuclei of the polymer, containing about ten HbS molecules, form. In search of novel control parameters for processes occurring on the nanoscale, we explore the role of free heme, excessively released in sickle erythrocytes. We show that dialysis of small-molecules out of HbS solutions completely prevents HbS polymerization. The addition of micromolar concentrations of heme to dialyzed solutions leads to rates and delay times for nucleation and polymer fiber growth rates faster by two orders of magnitude than prior to dialysis. We show that free heme enhances the attraction between HbS molecules and increases by two orders of magnitude the volume of the metastable clusters of dense HbS liquid, the locations where HbS polymer nuclei form. These results suggest that variation of the free heme concentration in the erythrocytes may be a major factor for the puzzling complexity of the clinical manifestations of sickle cell anemia. The removal of free heme from the erythrocyte cytosol may be an avenue to sickle cell disease therapy.