Allosteric and cooperative interactions are fundamental to many biological processes. Hemoglobin represents the paradigm example of allosterism. However, despite 100 years of study a clear picture of how hemoglobin manifests it cooperative oxygen binding behavior in terms of energetic interactions has remained elusive. To address the complexity of systems such as hemoglobin, the concept of hierarchical thermodynamic interactions between subsequent events has been developed. This method allows the thermodynamic interactions in systems with multiple interacting events to be systematically dissected, and has been applied to systems ranging from polyprotic acids and bases to the oxygen binding properties of hemoglobin. Application of this approach to hemoglobin results in a relatively simple model requiring only a few terms, and which is highly symmetrical in terms of the thermodynamic interactions between subunits. Given that hemoglobin is under substantial evolutionary pressure, why would hemoglobin adopt such a functional model? When considered from a functional optimization perspective, the resulting simple hierarchical model is that expected for a nearly perfect allosteric oxygen binding protein within the constraint of hemoglobin's global structure. This analysis addresses a longstanding problem in biochemistry, and further demonstrates the concept of hierarchical interactions for the analysis and interpretation of data pertaining to complex and difficult thermodynamic problems.

Hierarchical interaction approach to thermodynamic complexity: Demonstration of allosteric perfection in hemoglobin

248th National Meeting (2014)

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