The Physical Chemistry of Sickle Cell Anemia
Peter G. Vekilov, Professor of Chemical and Biomolecular Engineering and Chemistry, University of Houston, Texas
Friday, October 31, 2008
This seminar is part of the Jones Seminars on Science, Technology, and Society series
Sickle cell anemia is a debilitating genetic disease, which affects hundreds of thousands of babies born each year worldwide. Its primary pathogenic event is the formation of long fibers (with 14 molecules in the cross section) of a mutant, sickle cell, hemoglobin (HbS). Fiber formation is a first order phase transition, and, thus, sickle cell anemia is one of a line of diseases (Alzheimer's, Huntington's, prion, etc.) in which nucleation initiates pathophysiology. We show that the fiber growth follows a first-order, Kramers-type kinetics model. The value of the entropy of the transition state for incorporation into a fiber suggests that this entropy is due to the release of the last layer of water molecules structured around contact sites on the surface of the HbS molecules. As a result of this entropy gain, the free-energy barrier for incorporation of HbS molecules into a fiber is negligible and fiber growth unprecedentedly fast. We also 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 presence of a precursor in the HbS nucleation mechanism allows low-concentration solution components to strongly affect the nucleation kinetics. We show that free heme, excessively released in sickle erythrocytes due to autooxidation, leads to orders of magnitude faster nucleation and that its removal prevents polymerization. These findings suggest that variations of the concentrations of the components of the red cell cytosol, e.g., heme, 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.
- J. Mol. Biol. 365, 425 (2007)
- Biophys. J. 92, 902 (2007)
- Biophys. J. 92, 267 (2007)
- Brit. J. Haematol. 139, 173 (2007)
- J. Mol. Biol. 377, 882 (2008)
About the Speaker
Peter G. Vekilov received his Ph.D. in 1991 from the Russian Academy of Sciences, Institute of Crystallography, under advice from A.A. Chernov. After postdoctoral stints in Sofia, Bulgaria, Tsukuba, Japan, and Huntsville, Alabama, he was an Assistant Professor of Chemistry at the University in Alabama in Huntsville. Since 2001, he has been an Associate Professor and, since 2007, Professor of Chemical and Biomolecular Engineering and of Chemistry at the University of Houston. His main research interests are in the area of phase transitions in protein solutions. He has studied their thermodynamic aspects, including intermolecular interactions and phase diagrams and has demonstrated the existence of mesoscopic metastable phases. Nucleation kinetics and mechanisms have been a major focus of study, and a two-step mechanism, involving a metastable dense liquid precursor has been put forth. Molecular mechanisms of crystallization of protein and other materials form solution have been elucidated, highlighting the role of water structuring for the determination of the rate of the process. He is the recipient of the 2006 UH Excellence in Research and Scholarship Award, 2002 DuPont Research Award, 2001 UAH Foundation Research and Creative Achievement Award, 1995 International Union of Crystallography Young Scientist Award, among others. He is a member of the US National Committee for Crystallography, the executive councils of the International Organization for Biological Crystallization and the American Association for Crystal Growth, he has organized and chaired numerous conferences and symposia and served as a chair of the 2007 Gordon Conference on Thin Film and Crystal Growth Mechanisms.