THE STEREOCHEMICAL MECHANISM OF THE COOPERATIVE EFFECTS IN HEMOGLOBINREVISITED

In 1970, Perutz tried to put the allosteric mechanism of hemoglobin, p roposed by Monod, Wyman and Changeux in 1965, on a stereochemical basi s. He interpreted their two-state model in terms of an equilibrium bet ween two alternative structures, a tense one (T) with low oxygen affin ity, constrained by salt-bridges between the C-termini of the four sub units, and a relaxed one (R) lacking these bridges. The equilibrium wa s thought to be governed primarily by the positions of the iron atoms relative to the porphyrin: out-of-plane in five-coordinated, high-spin deoxyhemoglobin, and in-plane in six-coordinated, low-spin oxyhemoglo bin. The tension exercised by the salt-bridges in the IT-structure was to be transmitted to the heme-linked histidines and to restrain the m ovement of the iron atoms into the porphyrin plane that is necessary f or oxygen binding. At the B-hemes, the distal valine and histidine blo ck the oxygen-combining site in the T-structure; its tension was thoug ht to strengthen that blockage. Finally, Perutz attributed the lineari ty of proton release with early oxygen uptake to the sequential ruptur e of salt-bridges in the T-structure and to the accompanying drop in p Ka of the weak bases that form part of them. Almost every feature of t his mechanism has been disputed, but evidence that has come to light m ore than 25 years later now shows it to have been substantially correc t. That new evidence is reviewed below.