Abstract
The study of complex macromolecular binding systems reveals that a high number of states and processes are involved in their mechanism of action, as has become more apparent with the sophistication of the experimental techniques used. The resulting information is often difficult to interpret because of the complexity of the scheme (large size and profuse interactions, including cooperative and self-assembling interactions) and the lack of transparency that this complexity introduces into the interpretation of the indexes traditionally used to describe the binding properties. In particular, cooperative behaviour can be attributed to very different causes, such as direct chemical modification of the binding sites, conformational changes in the whole structure of the macromolecule, aggregation processes between different subunits, etc. In this paper, we propose a novel approach for the analysis of the binding properties of complex macromolecular and self-assembling systems. To quantify the binding behaviour, we use the global association quotient defined as K c = [occupied sites]/([free sites] L), L being the free ligand concentration. K c can be easily related to other measures of cooperativity (such as the Hill number or the Scatchard plot) and to the free energies involved in the binding processes at each ligand concentration. In a previous work, it was shown that Kc could be decomposed as an average of equilibrium constants in two ways: intrinsic constants for Adair binding systems and elementary constants for the general case. In this study, we show that these two decompositions are particular cases of a more general expression, where the average is over partial association quotients, associated with subsystems from which the system is composed. We also show that if the system is split into different subsystems according to a binding hierarchy that starts from the lower, microscopic level and ends at the higher, aggregation level, the global association quotient can be decomposed following the hierarchical levels of macromolecular organisation. In this process, the partial association quotients of one level are expressed, in a recursive way, as a function of the partial quotients of the level that is immediately below, until the microscopic level is reached. As a result, the binding properties of very complex macromolecular systems can be analysed in detail, making the mechanistic explanation of their behaviour transparent. In addition, our approach provides a model-independent interpretation of the intrinsic equilibrium constants in terms of the elementary ones.
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Acknowledgements
JLG and FM acknowledge the support of this research by the Spanish Ministry of Education and Science (DGICYT: Projects BQU2003-09698 and CTM2006-13583) and by the “Comissionat d’Universitats i Recerca” of the Generalitat de Catalunya. LA and EM acknowledge support from Programa de Desarrollo de las Ciencias Básicas (PEDECIBA, Montevideo). FM and LA are grateful to AECI, Universidad de la República (Montevideo) and Universitat de Barcelona under the “Programa de Cooperación Interuniversitaria (España-América Latina)” for financial support.
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Garcés, J.L., Acerenza, L., Mizraji, E. et al. A Hierarchical Approach to Cooperativity in Macromolecular and Self-Assembling Binding Systems. J Biol Phys 34, 213–235 (2008). https://doi.org/10.1007/s10867-008-9116-x
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DOI: https://doi.org/10.1007/s10867-008-9116-x