Thermal (Or Endothermic) Aggregation of Sickle Cell Hemoglobin (Hb S) During Sickling

  • Makio Murayama
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 28)


The human hemoglobin molecule consists of 4 polypeptide chains, one pair designated the α’s and the other the β’s. Sickle cell hemoglobin (Hb S) differs from the normal by a single amino acid substitution at the 6th position in each β chain. It further appears that there is a hydrophobic pocket in each of the a chains which is complementary to the β-6-Valyl region, allowing deoxygenated sickle cell hemoglobin (Hb S) tetramers to stack by hydrophobic interactions. When oxygenated, the β chains move closer to each other by about 5 angstroms and the stacking crumbles because the goodness of fit is lost, This is unsickling by conformational change. There is another unsickling mechanism which involves an entropy change. In 1957 I reported that Hb S has a negative temperature coefficient of aggregation, i.e., a deoxygenated Hb S solution at 0° gels when warmed to 38° C but liquefies reversibly when replaced in the ice bath. Thus, the sickling phenomenon involves a thermal (or endothermic) aggregation of Hb S. The energy of activation for this reaction (ΔH*) is 17.3 kCal mole-1 and the entropy change amounts to 55 e. u. It appears reasonable to assume that the same entropy change is required to set a molecule of water free from the hydration layer about the hydrophobic residues as is required in the melting of ice.


Entropy Change Tobacco Mosaic Virus Hydration Layer Negative Temperature Coefficient Thermal Aggregation 
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  1. Bray, H. G., and White, K. (1966) Kinetics and thermodynamics in biochemistry. Academic Press, Inc., New York. 169–170.Google Scholar
  2. Hamann, S. D. (1957). Physico-Chemical Effects of Pressure. Butterworth, London.Google Scholar
  3. Huisman, T. H., and Dozy, A. M. (1965). Studies on the heterogeneity of Hemoglobin IX. The use of tri(hydroxymethyl)-aminomethane HCl buffers in the anion-exchange chromatography of hemoglobins. J. Chromateg., 19: 160–169.CrossRefGoogle Scholar
  4. Kauzmann, W. (1959). Some factors in the interpretation of protein denaturation. Advances in protein chemistry. Edited by C. B. Anfinsen, Jr., M. L. Anson, K. Bailey, J. T. Edsall, Academic Press Vol. 14: 1–63.Google Scholar
  5. Kettman, H. S., Nishikawa, A. H., Morita, R. Y., and Becker, R. R. (1966). Effect of hydrostatic pressure on the aggregation reaction of poly-L-Valyl-Ribonuclease. Biochem. and Biophys. Research Communications 22: 262–267.Google Scholar
  6. Kliman, H. L. (1970). The solubility of 4-octanone in water, a model compound study of hydrophobic interactions at high pressure. Princeton University Press Thesis.Google Scholar
  7. Lauffer, H. A. (1964). Protein-protein interaction: Endothermic polymerization and biological processes in proteins and their reactions. Edited by Schultz, H. W., and Anglemier, A. F., The Avi Publishing Co., Inc., Westport, Conn. pp. 87–116.Google Scholar
  8. Murayama, M. (1957). Titratable sulfhydryl groups of normal and sickle cell hemoglobin at 0° and 38°. J. Biol. Chem., 228: 231–240.PubMedGoogle Scholar
  9. Murayama, M. (1966). Molecular mechanism of human red cell sickling. Science 153: 143–149.CrossRefGoogle Scholar
  10. Murayama, M., and Hasegawa, F. (1969). Effect of hydrostatic pressure on the aggregation of human sickle cell hemoglobin at 37°. Fed. Proc. 28: 536 (abst.).Google Scholar
  11. Oster, G. (1947). Light scattering from polymerizing and coagulating systems. J. Colloid Sci. 2: 291–299.CrossRefGoogle Scholar
  12. Schade, A. L., and Reinhart, R. W. (1970). Galactothermin, a reversibly heat-precipitable protein of human milk at neutral pH. Biochem. J. 118: 181–186.PubMedGoogle Scholar
  13. Smith, M. H. M. (1961). Modified cuvettes for photoelectric spectrophotometry. Nature 192: 722–725.PubMedCrossRefGoogle Scholar
  14. Weale, K. E. (1967). Chemical reactions at high pressures. E. and E. Spon, Ltd., London.Google Scholar

Copyright information

© Plenum Press, New York 1972

Authors and Affiliations

  • Makio Murayama
    • 1
  1. 1.National Institutes of HealthBethesdaUSA

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