Molecular Models for Cooperativity and Allosteric Interactions

Abstract

Up to this point we have discussed cooperativity only in thermodynamic terms without making any assumptions about molecular mechanisms. It is, however, clear that deriving molecular models for cooperativity will allow one to gain insight into the molecular events which may play a role in bringing about the large variety of cooperative phenomena. Furthermore, defining molecular parameters which may describe cooperative phenomena may help to design experiments to explore the mechanism of cooperativity. Any model describing cooperativity makes use of basic experimental findings. In the development of molecular models to explain cooperativity, hemoglobin played a key role. As early as 1935 Pauling made a serious attempt to explain the cooperative oxygen binding to hemoglobin in terms of site-site interactions. Pauling (1935) used a restricted Adair scheme and postulated that the progressive increase in oxygen affinity is brought about by a direct interaction between the heme groups. It took many years to demonstrate that Pauling’s model was incorrect, since the heme groups are too far apart in the protein molecule to interact directly. Both the X-ray crystallographic studies of Perutz (1970, 1972), and a variety of spectroscopic techniques revealed that the structure of the heme groups remains unchanged, whereas the structure of the protein is changed upon oxygen ligation.