Evaluation of rate law approximations in bottom-up kinetic models of metabolism

Bin Du, Daniel C. Zielinski, Erol S. Kavvas, Andreas Draeger, Justin Tan, Zhen Zhang, Kayla E. Ruggiero, Garri A. Arzumanyan, Bernhard Palsson

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Abstract

Background: The mechanistic description of enzyme kinetics in a dynamic model of metabolism requires specifying the numerical values of a large number of kinetic parameters. The parameterization challenge is often addressed through the use of simplifying approximations to form reaction rate laws with reduced numbers of parameters. Whether such simplified models can reproduce dynamic characteristics of the full system is an important question. Results: In this work, we compared the local transient response properties of dynamic models constructed using rate laws with varying levels of approximation. These approximate rate laws were: 1) a Michaelis-Menten rate law with measured enzyme parameters, 2) a Michaelis-Menten rate law with approximated parameters, using the convenience kinetics convention, 3) a thermodynamic rate law resulting from a metabolite saturation assumption, and 4) a pure chemical reaction mass action rate law that removes the role of the enzyme from the reaction kinetics. We utilized in vivo data for the human red blood cell to compare the effect of rate law choices against the backdrop of physiological flux and concentration differences. We found that the Michaelis-Menten rate law with measured enzyme parameters yields an excellent approximation of the full system dynamics, while other assumptions cause greater discrepancies in system dynamic behavior. However, iteratively replacing mechanistic rate laws with approximations resulted in a model that retains a high correlation with the true model behavior. Investigating this consistency, we determined that the order of magnitude differences among fluxes and concentrations in the network were greatly influential on the network dynamics. We further identified reaction features such as thermodynamic reversibility, high substrate concentration, and lack of allosteric regulation, which make certain reactions more suitable for rate law approximations. Conclusions: Overall, our work generally supports the use of approximate rate laws when building large scale kinetic models, due to the key role that physiologically meaningful flux and concentration ranges play in determining network dynamics. However, we also showed that detailed mechanistic models show a clear benefit in prediction accuracy when data is available. The work here should help to provide guidance to future kinetic modeling efforts on the choice of rate law and parameterization approaches.
Original languageEnglish
Article number40
JournalBMC Systems Biology
Volume10
Number of pages15
ISSN1752-0509
DOIs
Publication statusPublished - 2016

Bibliographical note

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Keywords

  • Approximate rate laws
  • Kinetic modeling
  • Mass action kinetics
  • Metabolic modeling
  • Michaelis-Menten kinetics

Cite this

Du, B., Zielinski, D. C., Kavvas, E. S., Draeger, A., Tan, J., Zhang, Z., Ruggiero, K. E., Arzumanyan, G. A., & Palsson, B. (2016). Evaluation of rate law approximations in bottom-up kinetic models of metabolism. BMC Systems Biology, 10, [40]. https://doi.org/10.1186/s12918-016-0283-2