The two-state allosteric model of Monod, Wyman, and Changeux (MWC) provides an excellent description of homotropic effects in a vast array of equilibrium and kinetic measurements on cooperative ligand binding by hemoglobin. However, in contrast to experimental observations, the model does not allow for alteration of the ligand affinity of the T quaternary structure by allosteric effectors. This failure to explain heterotropic effects has been appreciated for over 30 years, and it has been generally assumed to result from tertiary conformational changes in the absence of a quaternary change. Here we explore a model that preserves the essential MWC idea that binding without a quaternary conformational change is non-cooperative, but where tertiary conformations of individual subunits play the primary role instead of the quaternary conformations. In this model, which we call the 'tertiary two-state (TTS) model', the two affinity states correspond to two tertiary conformations of individual subunits rather than the two quaternary conformations of the MWC two-state allosteric model. Ligation and the R quaternary structure bias the subunit population toward the high affinity tertiary conformation, while deligation and the T quaternary structure favor the low affinity tertiary conformation. We show that the model is successful in quantitatively explaining a demanding set of kinetic data from nanosecond carbon monoxide photodissociation experiments at times longer than similar to1 mus. Better agreement between the model and the submicrosecond kinetic data may result from detailed considerations of the distribution and dynamics of conformational substates of the two tertiary conformations. The model is consistent with the results of solution, gel, and single crystal oxygen binding studies, but underestimates the population of doubly-liganded molecules determined in low-temperature electrophoresis experiments.
A Tertiary Two-state Allosteric Model for Hemoglobin / HENRY E. R.; BETTATI S.; HOFRICHTER J.; EATON W. A.. - In: BIOPHYSICAL CHEMISTRY. - ISSN 0301-4622. - 98:1-2(2002), pp. 149-164. [10.1016/S0301-4622(02)00091-1]
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