A general framework for thermodynamically consistent parameterization and efficient sampling of enzymatic reactions

Saa, Pedro and Nielsen, Lars K. (2015) A general framework for thermodynamically consistent parameterization and efficient sampling of enzymatic reactions. PLoS Computational Biology, 11 4: 1-25. doi:10.1371/journal.pcbi.1004195

Author Saa, Pedro
Nielsen, Lars K.
Title A general framework for thermodynamically consistent parameterization and efficient sampling of enzymatic reactions
Journal name PLoS Computational Biology   Check publisher's open access policy
ISSN 1553-7358
Publication date 2015-04-14
Sub-type Article (original research)
DOI 10.1371/journal.pcbi.1004195
Open Access Status DOI
Volume 11
Issue 4
Start page 1
End page 25
Total pages 25
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2016
Language eng
Formatted abstract
Kinetic models provide the means to understand and predict the dynamic behaviour of enzymes upon different perturbations. Despite their obvious advantages, classical parameterizations require large amounts of data to fit their parameters. Particularly, enzymes displaying complex reaction and regulatory (allosteric) mechanisms require a great number of parameters and are therefore often represented by approximate formulae, thereby facilitating the fitting but ignoring many real kinetic behaviours. Here, we show that full exploration of the plausible kinetic space for any enzyme can be achieved using sampling strategies provided a thermodynamically feasible parameterization is used. To this end, we developed a General Reaction Assembly and Sampling Platform (GRASP) capable of consistently parameterizing and sampling accurate kinetic models using minimal reference data. The former integrates the generalized MWC model and the elementary reaction formalism. By formulating the appropriate thermodynamic constraints, our framework enables parameterization of any oligomeric enzyme kinetics without sacrificing complexity or using simplifying assumptions. This thermodynamically safe parameterization relies on the definition
of a reference state upon which feasible parameter sets can be efficiently sampled. Uniform sampling of the kinetics space enabled dissecting enzyme catalysis and revealing the impact of thermodynamics on reaction kinetics. Our analysis distinguished three reaction elasticity regions for common biochemical reactions: a steep linear region (0>ΔGr>-2 kJ/
mol), a transition region (-2>ΔGr>-20 kJ/mol) and a constant elasticity region (ΔGr<-20 kJ/mol). We also applied this framework to model more complex kinetic behaviours such as the monomeric cooperativity of the mammalian glucokinase and the ultrasensitive response of the phosphoenolpyruvate carboxylase of Escherichia coli. In both cases, our approach described appropriately not only the kinetic behaviour of these enzymes, but it also provided insights about the particular features underpinning the observed kinetics. Overall, this framework will enable systematic parameterization and sampling of enzymatic reactions.
Keyword Kinetic models
Thermodynamically consistent parameterization
Enzymatic reactions
General reaction assembly and sampling platform
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Australian Institute for Bioengineering and Nanotechnology Publications
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Citation counts: TR Web of Science Citation Count  Cited 4 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 5 times in Scopus Article | Citations
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