Incorporation of flexible objectives and time-linked simulation with flux balance analysis

We present two modifications of the flux balance analysis (FBA) metabolic modeling framework which relax implicit assumptions of the biomass reaction. Our flexible flux balance analysis (flexFBA) objective removes the fixed proportion between reactants, and can therefore produce a subset of biomass...

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Bibliographic Details
Published in:Journal of theoretical biology 2014-03, Vol.345, p.12-21
Main Authors: Birch, Elsa W., Udell, Madeleine, Covert, Markus W.
Format: Article
Language:English
Subjects:
Animals
Biomass
Computer Simulation
Gene Knockout Techniques
Integrated modeling
Metabolic Networks and Pathways - genetics
Metabolic Networks and Pathways - physiology
Metabolism
Models, Biological
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Summary:We present two modifications of the flux balance analysis (FBA) metabolic modeling framework which relax implicit assumptions of the biomass reaction. Our flexible flux balance analysis (flexFBA) objective removes the fixed proportion between reactants, and can therefore produce a subset of biomass reactants. Our time-linked flux balance analysis (tFBA) simulation removes the fixed proportion between reactants and byproducts, and can therefore describe transitions between metabolic steady states. Used together, flexFBA and tFBA model a time scale shorter than the regulatory and growth steady state encoded by the biomass reaction. This combined short-time FBA method is intended for integrated modeling applications to enable detailed and dynamic depictions of microbial physiology such as whole-cell modeling. For example, when modeling Escherichia coli, it avoids artifacts caused by low-copy-number enzymes in single-cell models with kinetic bounds. Even outside integrated modeling contexts, the detailed predictions of flexFBA and tFBA complement existing FBA techniques. We show detailed metabolite production of in silico knockouts used to identify when correct essentiality predictions are made for the wrong reason. •The rigid flux balance analysis (FBA) biomass reaction hinders whole-cell modeling.•New flexible FBA can produce subsets of biomass reactants.•Time-linked FBA removes the reactant-to-byproduct long-time assumption.•Our new methods avoid low-copy enzyme metabolic artifacts for whole-cell modeling.
ISSN:0022-5193
1095-8541
DOI:10.1016/j.jtbi.2013.12.009