A General Framework for Thermodynamically Consistent Parameterization and Efficient Sampling of Enzymatic Reactions

A General Framework for Thermodynamically Consistent Parameterization and Efficient Sampling of Enzymatic Reactions

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 regulat...

Full description

Bibliographic Details
Main Authors: Saa, Pedro, Nielsen, Lars K.
Format: Online
Language:English
Published: Public Library of Science 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397067/
id pubmed-4397067
recordtype oai_dc
spelling pubmed-43970672015-04-21 A General Framework for Thermodynamically Consistent Parameterization and Efficient Sampling of Enzymatic Reactions Saa, Pedro Nielsen, Lars K. Research Article 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. Public Library of Science 2015-04-14 /pmc/articles/PMC4397067/ /pubmed/25874556 http://dx.doi.org/10.1371/journal.pcbi.1004195 Text en © 2015 Saa, Nielsen http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Saa, Pedro
Nielsen, Lars K.
spellingShingle Saa, Pedro
Nielsen, Lars K.
A General Framework for Thermodynamically Consistent Parameterization and Efficient Sampling of Enzymatic Reactions
author_facet Saa, Pedro
Nielsen, Lars K.
author_sort Saa, Pedro
title A General Framework for Thermodynamically Consistent Parameterization and Efficient Sampling of Enzymatic Reactions
title_short A General Framework for Thermodynamically Consistent Parameterization and Efficient Sampling of Enzymatic Reactions
title_full A General Framework for Thermodynamically Consistent Parameterization and Efficient Sampling of Enzymatic Reactions
title_fullStr A General Framework for Thermodynamically Consistent Parameterization and Efficient Sampling of Enzymatic Reactions
title_full_unstemmed A General Framework for Thermodynamically Consistent Parameterization and Efficient Sampling of Enzymatic Reactions
title_sort general framework for thermodynamically consistent parameterization and efficient sampling of enzymatic reactions
description 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.
publisher Public Library of Science
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397067/
_version_ 1613211740397371392

Similar Items