Sickle cell anemia is caused by the intracellular polymerization of sickle cell hemoglobin to form rod-like fibers. A knowledge of the fiber structure could be used for the design of an agent that could block fiber formation. We have combined the structure of hemoglobin (known from X-ray crystallography) and the molecular coordinates of the fiber (determined from electron microscopy) in order to synthesize a model which shows the intermolecular contacts of the fiber. This approach has allowed us to determine the contacts which form between molecules in the fiber. We are now studying how various mutations (some obtained by site directed mutagenesis) affect fiber structure. Such studies are expected to account for the structural and chemical properties of fibers in terms of intermolecular interactions.

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References:
Watowich, S., Gross L., and Josephs, R. (1989) Intermolecular Contacts within Sickle Hemoglobin Fibers. J. Mol. Biol. 209: 821-828.

M. R. Lewis, L. J. Gross, and R. Josephs. Variable Pitch in Frozen Hydrated Sickle Hemoglobin Fibers: An Image Analysis Model Study. Ultramicroscopy, 56 303-317 (1994).

Michael R. Lewis, Leon J. Gross, and Robert Josephs. Cryo- Electron Microscopy of Deoxy-Sickle Hemoglobin Fibers. Microscopy Research and Technique 27 459 - 467 (1994).

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