Two-step mechanism of homogeneous nucleation of sickle cell hemoglobin polymers
Oleg Galkin 1, Weichun Pan 1, Luis Filobelo 1, Rhoda Hirsch 2, Ronald Nagel 2 and Peter G Vekilov 1*
1 University of Houston
2 Albert Einstein College of Medicine
* To whom correspondence should be addressed. E-mail: vekilov{at}uh.edu.
Submitted on December 24, 2006
Revised on January 24, 2007
Accepted on 15 February 2007
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Abstract |
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Sickle cell anemia is a debilitating genetic disease, which affects hundreds of thousands 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 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.
Key Words:
HbS polymerization, dense liquid clusters, hemoglobin, nucleation mechanism, polarized light, sickel cell anemia
