Proton NMR studies of the molecular basis for the anti-sickling activity of non-covalent antisickling compounds.
Two new techniques of nuclear magnetic resonance spectroscopy are proposed to identify and characterize the binding sites of antisickling compounds to Hb S: measurements of the longitudinal relaxation rates (T1(-1)) of the C2 protons of individual surface histidyl residues of the C2 protons of individual surface histidyl residues of Hb S and intermolecular transferred nuclear Overhauser effects from protons in the heme pockets of the Hb S molecule. Using these methods, we have investigated the binding sites of L-phenylalanine, L-tryptophan, L-valine, and p-bromobenzylalcohol to sickle hemoglobin. With the exception of L-valine, all of these molecules are known to inhibit the polymerization of deoxy Hb S. We have found that for the compounds with antisickling activity, there are at least two binding sites to the Hb S molecule, one at or near the heme pockets of the alpha and beta chains and the other one in the vicinity of the beta 6 mutation site.
D000986:Antisickling Agents; D001592:Benzyl Alcohols; D001665:Binding Sites; D055598:Chemical Phenomena; D002621:Chemistry; D006451:Hemoglobin, Sickle; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010649:Phenylalanine; D014364:Tryptophan; D014633:Valine
D000986:Antisickling Agents; D001592:Benzyl Alcohols; D006451:Hemoglobin, Sickle; C038875:deoxyhemoglobin, sickle; D010649:Phenylalanine; C048038:4-bromobenzyl alcohol; D014364:Tryptophan; D014633:Valine