Improved Metabolic Models for E. coli and Mycoplasma genitalium from GlobalFit, an Algorithm That Simultaneously...

Constraint-based metabolic modeling methods such as Flux Balance Analysis (FBA) are routinely used to predict the effects of genetic changes and to design strains with desired metabolic properties. The major bottleneck in modeling genome-scale metabolic systems is the establishment and manual curation of reliable stoichiometric models. Initial reconstructions are typically refined through comparisons to experimental growth data from gene knockouts or nutrient environments. Existing methods iteratively correct one erroneous model prediction at a time, resulting in accumulating network changes that are often not globally optimal. We present GlobalFit, a bi-level optimization method that finds a globally optimal network, by identifying the minimal set of network changes needed to correctly predict all experimentally observed growth and non-growth cases simultaneously. When applied to the genome-scale metabolic model of Mycoplasma genitalium, GlobalFit decreases unexplained gene knockout phenotypes by 79%, increasing accuracy from 87.3% (according to the current state-of-the-art) to 97.3%. While currently available computers do not allow a global optimization of the much larger metabolic network of E. coli, the main strengths of GlobalFit are already played out when considering only one growth and one non-growth case simultaneously. Application of a corresponding strategy halves the number of unexplained cases for the already highly curated E. coli model, increasing accuracy from 90.8% to 95.4%.