Understanding FBA Solutions under Multiple Nutrient Limitations

Genome-scale stoichiometric modeling methods, in particular Flux Balance Analysis (FBA) and variations thereof, are widely used to investigate cell metabolism and to optimize biotechnological processes. Given (1) a metabolic network, which can be reconstructed from an organism's genome sequence, and (2) constraints on reaction rates, which may be based on measured nutrient uptake rates, FBA predicts which reactions maximize an objective flux, usually the production of cell components. Although FBA solutions may accurately predict the metabolic behavior of a cell, the actual flux predictions are often hard to interpret. This is especially the case for conditions with many constraints, such as for organisms growing in rich nutrient environments: it remains unclear why a certain solution was optimal. Here, we rationalize FBA solutions by explaining for which properties the optimal combination of metabolic strategies is selected. We provide a graphical formalism in which the selection of solutions can be visualized; we illustrate how this perspective provides a glimpse of the logic that underlies genome-scale modeling by applying our formalism to models of various sizes.