Sickle-cell hydrophobic interactions

Figure 3.14 Sickle-cell hemoglobin molecules polymerize due to the hydrophobic patch introduced by the mutation Glu 6 to Val in the P chain. The diagram (a) illustrates how this hydrophobic patch (green interacts with a hydrophobic pocket (red) in a second hemoglobin molecule, whose hydrophobic patch interacts with the pocket in a third molecule, and so on. Electron micrographs of sickle-cell hemoglobin fibers are shown in cross-section in (b) and along the fibers in (c). [(b) and (c) from J.T. Finch et al., Proc. Natl. Acad. Set. USA 70 718-722, 1973.)...

Aromatic side chains of amino acids such as phenylalanine, tryptophan, and tyrosine are found in general in the interior of proteins, in hydrophobic regions. In some proteins they mediate helix-helix contacts. It is to be expected that agents containing aromatic groups could interact with proteins via aromatic-aromatic interactions, as for instance, proven by X-ray studies of biphenyl compounds which inhibit sickle-cell hemoglobin gelation. 

If hydrophobic interactions are involved in this association, as has been suggested by Eauzmann (1959) on the basis of this observation, it should be sensitive to the introduction of small amounts of the appropriate weakly protic nonaqueous solvents. The endothermic association of sickle cell anemia hemoglobin (Murayama, 1956) is another case to investigate. 

Understanding of the sickling process and of the structure of the HbS polymer provides a rational basis for ways of correcting the molecular defect. Thus, dilution of the HbS in the red cells, blockage of the interaction of the y86 valine with the hydrophobic pocket, and decrease of... 

The hydrophobic effect is at veork here. The valine side chain on the surface seeks to avoid water and finds that it can make favorable van der Waals interactions veith the leucine and phenylalanine side chains on another deoxy molecule. The effect is to reduce the solubility of the deoxyhemoglogin and cause the crystallization of long fibers that distort the shapes of the red blood cells into the sickled motif. 

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