Molecular architecture of the fibers of sickle (SS) hemoglobin.

Abstract

Direct observations by electron microscopy and image reconstruction on the fibers of hemoglobin S responsible for sickling have revealed a complex, solid-core structure with 14 filaments that appear to be arranged in seven pairs of double filaments. Several lines of evidence indicate a close correspondence between these helical double filaments and the linear double filaments that occur in crystals of hemoglobin S. An analysis of the movements that would be required to interconvert fibers and crystals (and the consequences for the intermolecular contacts) has recently been completed. The movements have been described in terms of three rotation angles, the largest of which involves a rotation of 12 degrees between adjacent molecules in opposite strands of the double filaments. The detailed topology of the molecular contacts within the fibers has been described in terms of a series of surface maps based on polar coordinates. The coincidence of various intermolecular contact sites for the fibers with particular amino acid residues has permitted roles to be proposed for almost all sites where secondary mutations are known to perturb fiber formation. Current efforts to test the premises and conclusions of this analysis are described. Overall, these studies should pinpoint sites on the surface of hemoglobin S that are most suitable as targets for antisickling agents.