Sickle cell disease arises because of polymerization via a double nucleation mechanism involving homogeneous nucleation in solution and heterogeneous nucleation onto sickle hemoglobin polymer surfaces. The polymers form a gel that ultimately leads to capillary occlusion. This work will continue testing the description of heterogeneous nucleation developed in the last grant period. Nucleation rates on HbF mixtures with HbS will be measured and compared with the improved theories we have now developed. We will test our structural model by studies on modified and mutant hemoglobins. (provided by Dr. Adachi and Dr. Manning) The Overall aim is to produce a structurally motivated, computationally accurate model for gelation kinetics. In the studies in the last grant period it has become apparent that vibrational freedom of molecules within the aggregate expert profound control over the rate of polymerization. We will measure nucleation rates for several mutants, which are expected to affect the vibrational entropy. Finally we will begin experiments using particle-tracking- correlation techniques to probe the microrheology of gels as a function of domain size, polymer mass, and kinetics of formation. This will address a major gap in understanding, viz. how the well-described molecular events relate to the rigidity of the polymer mass formed. Rigidity of the gels will be compared with the vibrational entropy deduced above.
| Yosmanovich, Donna; Rotter, Maria; Aprelev, Alexey et al. (2016) Calibrating Sickle Cell Disease. J Mol Biol 428:1506-14 |
| Tokarev, Alexander; Aprelev, Alexey; Zakharov, Mikhail N et al. (2012) Multifunctional magnetic rotator for micro and nanorheological studies. Rev Sci Instrum 83:065110 |
| Weng, Weijun; Ferrone, Frank A (2011) Metastable gels: A novel application of Ogston theory to sickle hemoglobin polymers. Biophys Chem 154:99-101 |
| Rotter, Maria; Yosmanovich, Donna; Briehl, Robin W et al. (2011) Nucleation of sickle hemoglobin mixed with hemoglobin A: experimental and theoretical studies of hybrid-forming mixtures. Biophys J 101:2790-7 |
| Rotter, Maria A; Chu, Haiyan; Low, Philip S et al. (2010) Band 3 catalyzes sickle hemoglobin polymerization. Biophys Chem 146:55-9 |
| Zakharov, Mikhail N; Aprelev, Alexey; Turner, Matthew S et al. (2010) The microrheology of sickle hemoglobin gels. Biophys J 99:1149-56 |
| Weng, Weijun; Aprelev, Alexey; Briehl, Robin W et al. (2008) Universal metastability of sickle hemoglobin polymerization. J Mol Biol 377:1228-35 |
| Aprelev, Alexey; Weng, Weijun; Zakharov, Mikhail et al. (2007) Metastable polymerization of sickle hemoglobin in droplets. J Mol Biol 369:1170-4 |
| Adachi, Kazuhiko; Ding, Min; Surrey, Saul et al. (2006) The Hb A variant (beta73 Asp-->Leu) disrupts Hb S polymerization by a novel mechanism. J Mol Biol 362:528-38 |
| Rotter, Maria A; Aprelev, Alexey; Dragos, Dana et al. (2004) Aspartame has no effect on the polymerization of sickle hemoglobin. Clin Pharmacol Ther 75:248-9 |
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