Bayesian inference of metabolic kinetics from genome-scale multiomics data

PLoS Comput Biol. 2019 Nov 4;15(11):e1007424. doi: 10.1371/journal.pcbi.1007424. eCollection 2019 Nov.

Abstract

Modern biological tools generate a wealth of data on metabolite and protein concentrations that can be used to help inform new strain designs. However, learning from these data to predict how a cell will respond to genetic changes, a key need for engineering, remains challenging. A promising technique for leveraging omics measurements in metabolic modeling involves the construction of kinetic descriptions of the enzymatic reactions that occur within a cell. Parameterizing these models from biological data can be computationally difficult, since methods must also quantify the uncertainty in model parameters resulting from the observed data. While the field of Bayesian inference offers a wide range of methods for efficiently estimating distributions in parameter uncertainty, such techniques are poorly suited to traditional kinetic models due to their complex rate laws and resulting nonlinear dynamics. In this paper, we employ linear-logarithmic kinetics to simplify the calculation of steady-state flux distributions and enable efficient sampling and inference methods. We demonstrate that detailed information on the posterior distribution of parameters can be obtained efficiently at a variety of problem scales, including nearly genome-scale kinetic models trained on multiomics datasets. These results allow modern Bayesian machine learning tools to be leveraged in understanding biological data and in developing new, efficient strain designs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms
  • Bayes Theorem
  • Enzymes / metabolism*
  • Genomics / methods
  • Kinetics
  • Machine Learning
  • Metabolic Engineering / statistics & numerical data
  • Metabolism / physiology*
  • Metabolomics / methods*
  • Models, Biological

Substances

  • Enzymes

Grants and funding

This work was authored in part by Alliance for Sustainable Energy, LLC, the manager and operator of the National Renewable Energy Laboratory for the US Department of Energy (DOE) under contract no. DE-AC36-08GO28308. The views expressed in the article do not necessarily represent the views of the DOE or the US Government. We thank the US DOE Bioenergy Technologies Office for funding under contract DE-AC36–08GO28308 with the National Renewable Energy Laboratory. PCSJ was also partially funded by the Bioenergy Technologies Office Agile BioFoundry. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.