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Two-Step Mechanism of Homogeneous Nucleation of Sickle Cell Hemoglobin Polymers

Oleg Galkin ^*, Weichun Pan ^*, Luis Filobelo ^*, Rhoda Elison Hirsch  , Ronald L. Nagel  and Peter G. Vekilov ^* 

^* Department of Chemical and Biomolecular Engineering, and Department of Chemistry, University of Houston, Houston, Texas 77204-4004; and Department of Medicine (Division of Hematology), and Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, The Bronx, New York 10461

Correspondence: Address reprint requests to Peter G. Vekilov, E-mail: vekilov{at}uh.edu.

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.