Elimination of thermodynamically infeasible loops in steady-state metabolic models.

TitleElimination of thermodynamically infeasible loops in steady-state metabolic models.
Publication TypeJournal Article
Year of Publication2011
AuthorsSchellenberger J, Lewis NE, Palsson BØ
JournalBiophys J
Volume100
Issue3
Pagination544-53
PubMed Date2011-2-2
ISSN1542-0086
KeywordsEscherichia coli, Kinetics, Metabolic Networks and Pathways, Models, Biological, Monte Carlo Method, Thermodynamics
Abstract

The constraint-based reconstruction and analysis (COBRA) framework has been widely used to study steady-state flux solutions in genome-scale metabolic networks. One shortcoming of current COBRA methods is the possible violation of the loop law in the computed steady-state flux solutions. The loop law is analogous to Kirchhoff's second law for electric circuits, and states that at steady state there can be no net flux around a closed network cycle. Although the consequences of the loop law have been known for years, it has been computationally difficult to work with. Therefore, the resulting loop-law constraints have been overlooked. Here, we present a general mixed integer programming approach called loopless COBRA (ll-COBRA), which can be used to eliminate all steady-state flux solutions that are incompatible with the loop law. We apply this approach to improve flux predictions on three common COBRA methods: flux balance analysis, flux variability analysis, and Monte Carlo sampling of the flux space. Moreover, we demonstrate that the imposition of loop-law constraints with ll-COBRA improves the consistency of simulation results with experimental data. This method provides an additional constraint for many COBRA methods, enabling the acquisition of more realistic simulation results.

Alternate JournalBiophys. J.
PubMed ID21281568

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