The intracellular polymerization of deoxysickle hemoglobin is the primary cause of sickle cell anemia. During the past five years we have successfully solved the molecular structures of the sickle hemoglobin fiber and several other HbS polymers. These data on the fiber structure now offer an opportunity to investigate the factors responsible for stabilizing the fiber and promoting the transitions between the different HbS polymers. This *HI involve synthesizing a model of the fiber by combining the molecular coordinates obtained from electron microscopy with atomic resolution data from X-ray crystallography. Combining EM and X-ray data has the potential of providing a structural model at a higher resolution than would be possible using either technique alone. Moreover this approach is sufficiently general as to be applicable to other systems as well. We shall examine the effects of other mutations on the fiber structure (using electron microscopy). The structural changes will be correlated with changes in the kinetics of polymerization (measured with video microscopy) in order to determine how specific amino acid changes affect fiber formation. In parallel with the structural work on HbS polymers, we have been studying the effects of polymer formation on the red blood cell in order to better understand the complex chain of events which are initiated by fiber formation in vivo. We propose to investigate normal and irreversibly sickled skeletons and isolated skeletal proteins using negative staining and cryomicroscopy. Staining will provide information about the arrangement and interactions of the skeletal proteins' Cryomicroscopy will extend the resolution of the molecular image of the skeleton from 35 Angstroms (where substructure cannot be discerned) to 15 Angstroms or better where substructure can be resolved. This work will also include three dimensional reconstructions of stained and frozen-hydrated preparations of the skeletal proteins.