The funding of this proposed research will make it possible to develop a concerted attack to the problem of sickle cell anemia by two groups of investigators, who have pioneered (a) the use of cyanate in sickle cell anemia treatment (e.g. the Rockefeller group) and (b) the study of the chemical reactions of cyanate with hemoglobin (e.g. Dr. J. Kilmartin of MRC, Dept. of Molecular Biology, Cambridge, and Prof. L. Rossi-Bernardi of Milan University, Italy). The proposed research will produce a better picture than hitherto available of the functional properties of HbS. In fact, we believe that the systematic study of the effect of the various physiological ligands (e.g. carbon dioxide, protons, and organic phosphates) which are known to regulate the oxygen affinity of "sickle cell" blood and hemoglobin S represent an almost mandatory step in evaluating the changes induced by chemical modifications of the HbS molecule. Second, we shall prepare, by a new chromatographic method, large quantities of hemoglobin S in which key residues such as those responsible for 2,3-DPG and CO2 binding would be reacted with cyanate. We aim to produce a systematic investigation of the main changes in the physiological functions of such modified molecules by several physico-chemical techniques, both from the equilibrium and the kinetic point of view. Our approach should shed further light on the mechanism of gelling of HbS solutions, of sickling of "sickle cell" blood, and on the inhibitory effect of cyanate on such phenomena.