Abstract
Hemoglobin is a classical model allosteric protein. Research on hemoglobin parallels the development of key cooperativity and allostery concepts, such as the ‘all-or-none’ Hill formalism, the stepwise Adair binding formulation and the concerted Monod-Wymann-Changuex (MWC) allosteric model. While it is clear that the MWC model adequately describes the cooperative binding of oxygen to hemoglobin, rationalizing the effects of H+, CO2 or organophosphate ligands on hemoglobin-oxygen saturation using the same model remains controversial. According to the MWC model, allosteric ligands exert their effect on protein function by modulating the quaternary conformational transition of the protein. However, data fitting analysis of hemoglobin oxygen saturation curves in the presence or absence of inhibitory ligands persistently revealed effects on both relative oxygen affinity (c) and conformational changes (L), elementary MWC parameters. The recent realization that data fitting analysis using the traditional MWC model equation may not provide reliable estimates for L and c thus calls for a re-examination of previous data using alternative fitting strategies. In the current manuscript, we present two simple strategies for obtaining reliable estimates for MWC mechanistic parameters of hemoglobin steady-state saturation curves in cases of both evolutionary and physiological variations. Our results suggest that the simple MWC model provides a reasonable description that can also account for heterotropic interactions in hemoglobin. The results, moreover, offer a general roadmap for successful data fitting analysis using the MWC model.
Highlights
Hemoglobin is a classical model allosteric protein, with research on this protein mirroring the development of key cooperativity and allostery concepts [1,2,3,4,5,6,7]
How can reliable estimates for the L, KR and KT MWC mechanistic parameters of hemoglobin saturation curves be obtained? As pointed out above, reliable estimates for the Lc4 and LKR4 compound parameters can be obtained by fitting hermoglobin saturation data (Y" as a function of [S]) to a modified MWC equation [33]
Estimates for the values of the compound Lc4 and LKR4 and p50 parameters for 27 mammalian hemoglobin oxygen saturation curves, all obtained under similar physiological conditions, and for oxygen saturation curves of human hemoglobin obtained in a variety of experimental conditions (i.e., different pH, CO2 pressure and 2,3-bisphosphoglycerate (2,3-BPG) concentrations; the physiological dataset) were previously reported [33]
Summary
Hemoglobin is a classical model allosteric protein, with research on this protein mirroring the development of key cooperativity and allostery concepts [1,2,3,4,5,6,7]. The steady-state sigmoidal profile of oxygen binding to hemoglobin provided the basis for the ‘all-or-none’ Hill formulation offered in 1910 [8]. Adair proposed a phenomenological stepwise binding mechanism to account for hemoglobin saturation [9]. A seminal paper by Linus Pauling published ten years later was the first to suggest a structural or geometry-oriented explanation for cooperative oxygen binding by hemoglobin.
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