Uncertainty reduction in biochemical kinetic models: Enforcing desired model properties

PLoS Comput Biol. 2019 Aug 20;15(8):e1007242. doi: 10.1371/journal.pcbi.1007242. eCollection 2019 Aug.

Abstract

A persistent obstacle for constructing kinetic models of metabolism is uncertainty in the kinetic properties of enzymes. Currently, available methods for building kinetic models can cope indirectly with uncertainties by integrating data from different biological levels and origins into models. In this study, we use the recently proposed computational approach iSCHRUNK (in Silico Approach to Characterization and Reduction of Uncertainty in the Kinetic Models), which combines Monte Carlo parameter sampling methods and machine learning techniques, in the context of Bayesian inference. Monte Carlo parameter sampling methods allow us to exploit synergies between different data sources and generate a population of kinetic models that are consistent with the available data and physicochemical laws. The machine learning allows us to data-mine the a priori generated kinetic parameters together with the integrated datasets and derive posterior distributions of kinetic parameters consistent with the observed physiology. In this work, we used iSCHRUNK to address a design question: can we identify which are the kinetic parameters and what are their values that give rise to a desired metabolic behavior? Such information is important for a wide variety of studies ranging from biotechnology to medicine. To illustrate the proposed methodology, we performed Metabolic Control Analysis, computed the flux control coefficients of the xylose uptake (XTR), and identified parameters that ensure a rate improvement of XTR in a glucose-xylose co-utilizing S. cerevisiae strain. Our results indicate that only three kinetic parameters need to be accurately characterized to describe the studied physiology, and ultimately to design and control the desired responses of the metabolism. This framework paves the way for a new generation of methods that will systematically integrate the wealth of available omics data and efficiently extract the information necessary for metabolic engineering and synthetic biology decisions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Bayes Theorem
  • Biochemical Phenomena
  • Computational Biology
  • Hexokinase / metabolism
  • Kinetics
  • Machine Learning
  • Metabolic Engineering
  • Metabolic Networks and Pathways
  • Models, Biological*
  • Monte Carlo Method
  • Saccharomyces cerevisiae / metabolism
  • Uncertainty
  • Xylose / metabolism

Substances

  • Xylose
  • Hexokinase

Grants and funding

This work was supported by funding from the Ecole Polytechnique Fédérale de Lausanne (EPFL), the 2015/313 ERASysAPP RobustYeast Project funded through SystemsX.ch, the Swiss Initiative for Systems Biology evaluated by the Swiss National Science Foundation, and the Swiss National Science Foundation grant 315230_163423. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.