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Possible orientations of deoxyhemoglobin S molecules within sickle-cell fibers are delimited by polarized absorption measurements on single sickled cells and single crystals of deoxyhemoglobin A. The polarization ratio of cells provides a lower limit for that of an individual fiber and, coupled with the absorption properties of the deoxyhemoglobin molecule, restricts the orientation of the long molecular (x) axis to within 220 of the fiber axis. Adopting the stacked ring model of Finch et al. for the molecular positions and the additional constraint that at least one mutated (G6) site is part of an intermolecular contact, our optical result requires that the true molecular dyad (y) axis pass through some part of an adjacent molecule in the same ring. This range of orientations for the y axis is approximately perpendicular to those described in existing models and places at least one 36 residue in position to be part of a contact between molecules in the same ring.The deformation that accompanies the deoxygenation of erythrocytes from patients with sickle-cell anemia is believed to result from the aggregation of hemoglobin molecules into an ordered phase. Crystallinity is evident from the linear birefringence (1-6) and dichroism (7,8), and from the fibertype x-ray diffraction patterns (9) of sickled cells and gels of deoxyhemoglobin S. Electron-microscope studies (6,8,(10)(11)(12)(13)(14) indicate that the ordered phase is composed of bundles of long straight fibers, aligned parallel to each other as in a nematic liquid crystal. Finch et al. (8) have proposed a model for the individual fibers ( Fig. 1), which appears to be consistent with both the electron-microscope and x-ray diffraction results. In this model the fiber may be described as a microtubule constructed from stacked rings of six hemoglobin molecules, where each ring is rotated slightly relative to the one below it. The structure can alternatively be viewed as six intertwined helical filaments, each having about 48 hemoglobin molecules per turn. If this model for the molecular positions is correct, then a knowledge of the precise molecular orientation should define the role of the mutation sites [Glu A3(6)0--B Val] in forming intermolecular contacts within the fiber.Neither electron microscopy nor x-ray diffraction has provided any concrete information on the molecular orientation. The hemoglobin molecule is a slightly elongated spheroid of dimensions 65 X 55 X 50 i (15). The lack of significant shape anisotropy permits considerable freedom in packing hemoglobin molecules into a fiber of dimensions compatible with those found by electron microscopy and x-ray diffraction. In contrast to the physical ellipsoid, the ellipsoid that describes the absorption of plane-polarized light by a hemoglobin molecule is highly anisotropic (Fig. 2). One of the dimensions of this ellipsoid (x) is considerably shorter than the other two, and it is possible to obtain its precise orientation within the fiber from polarized absorption measurements. Visual observati...

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