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Metastable Mesoscopic Clusters in Solutions of Sickle-Cell Hemoglobin

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

^* Department of Chemical Engineering and Department of Chemistry, University of Houston, Houston, Texas 77204-4004; and Division of Hematology, Department of Medicine, 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 hemoglobin (HbS) is a mutant, whose polymerization while in deoxy state in the venous circulation underlies the debilitating sickle cell anemia. It has been suggested that the nucleation of the HbS polymers occurs within clusters of dense liquid, existing in HbS solutions. We use dynamic light scattering with solutions of deoxy-HbS, and, for comparison, of oxy-HbS and oxy-normal adult hemoglobin, HbA. We show that solutions of all three Hb variants contain clusters of dense liquid, several hundred nanometers in size, which are metastable with respect to the Hb solutions. The clusters form within a few seconds after solution preparation and their sizes and numbers remain relatively steady for up to 3 h. The lower bound of the cluster lifetime is 15 ms. The clusters exist in broad temperature and Hb concentration ranges, and occupy 10^–5–10^–2 of the solution volume. The results on the cluster properties can serve as test data for a potential future microscopic theory of cluster stability and kinetics. More importantly, if the clusters are a part of the nucleation mechanism of HbS polymers, the rate of HbS polymerization can be controlled by varying the cluster properties.

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