title: Two-step mechanism of homogeneous nucleation of sickle cell hemoglobin polymers.
abstract: Sickle cell anemia is a debilitating genetic disease that affects hundreds of thousands of babies born each year worldwide. Its primary pathogenic event is the polymerization of a mutant, sickle cell, hemoglobin (HbS); and this is one of a line of diseases (Alzheimer's, Huntington's, prion, etc.) in which nucleation initiates pathophysiology. We show that the homogeneous nucleation of HbS polymers follows a two-step mechanism with metastable dense liquid clusters serving as precursor to the ordered nuclei of the HbS polymer. The evidence comes from data on the rates of fiber nucleation and growth and nucleation delay times, the interaction of fibers with polarized light, and mesoscopic metastable HbS clusters in solution. The presence of a precursor in the HbS nucleation mechanism potentially allows low-concentration solution components to strongly affect the nucleation kinetics. The variations of these concentrations in patients might account for the high variability of the disease in genetically identical patients. In addition, these components can potentially be utilized for control of HbS polymerization and treatment of the disease.
authors: Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas 77204-4004, USA.
authors: Oleg
authors: O
authors: Galkin
authors: Weichun
authors: W
authors: Pan
authors: Luis
authors: L
authors: Filobelo
authors: Rhoda Elison
authors: RE
authors: Hirsch
authors: Ronald L
authors: RL
authors: Nagel
authors: Peter G
authors: PG
authors: Vekilov
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood; D004912:Erythrocytes / Q000737:chemistry; D006451:Hemoglobin, Sickle / Q000737:chemistry* / Q000302:isolation & purification; D006801:Humans; D007700:Kinetics; D046911:Macromolecular Substances / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation
chemical_list: D006451:Hemoglobin, Sickle; D046911:Macromolecular Substances