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Identifiability, reducibility, and adaptability in allosteric macromolecules

Bohner, G; Venkataraman, G; (2017) Identifiability, reducibility, and adaptability in allosteric macromolecules. Journal of General Physiology , 149 (5) pp. 547-560. 10.1085/jgp.201611751. Green open access

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Abstract

The ability of macromolecules to transduce stimulus information at one site into conformational changes at a distant site, termed “allostery,” is vital for cellular signaling. Here, we propose a link between the sensitivity of allosteric macromolecules to their underlying biophysical parameters, the interrelationships between these parameters, and macromolecular adaptability. We demonstrate that the parameters of a canonical model of the mSlo large-conductance Ca2+-activated K+ (BK) ion channel are non-identifiable with respect to the equilibrium open probability-voltage relationship, a common functional assay. We construct a reduced model with emergent parameters that are identifiable and expressed as combinations of the original mechanistic parameters. These emergent parameters indicate which coordinated changes in mechanistic parameters can leave assay output unchanged. We predict that these coordinated changes are used by allosteric macromolecules to adapt, and we demonstrate how this prediction can be tested experimentally. We show that these predicted parameter compensations are used in the first reported allosteric phenomena: the Bohr effect, by which hemoglobin adapts to varying pH.

Type: Article
Title: Identifiability, reducibility, and adaptability in allosteric macromolecules
Open access status: An open access version is available from UCL Discovery
DOI: 10.1085/jgp.201611751
Publisher version: http://doi.org/10.1085/jgp.201611751
Language: English
Additional information: © 2017 Bohner and Venkataraman http://www.rupress.org/terms/ https://creativecommons.org/licenses/by-nc-sa/4.0/ This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
Keywords: Science & Technology, Life Sciences & Biomedicine, Physiology, LIGAND-BINDING PARAMETERS, ION-CHANNEL KINETICS, MACROSCOPIC CURRENTS, MISSED EVENTS, BK CHANNEL, MODELS, VOLTAGE, EVOLVABILITY, ROBUSTNESS, ACTIVATION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Gatsby Computational Neurosci Unit
URI: http://discovery.ucl.ac.uk/id/eprint/10044669
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