Abstract
Mathematical models of biochemical networks are useful tools to understand and ultimately predict how cells utilize nutrients to produce valuable products. Hybrid cybernetic models in combination with elementary modes (HCM) is a tool to model cellular metabolism. However, HCM is limited to reduced metabolic networks because of the computational burden of calculating elementary modes. In this study, we developed the hybrid cybernetic modeling with flux balance analysis or HCM-FBA technique which uses flux balance solutions instead of elementary modes to dynamically model metabolism. We show HCM-FBA has comparable performance to HCM for a proof of concept metabolic network and for a reduced anaerobic E. coli network. Next, HCM-FBA was applied to a larger metabolic network of aerobic E. coli metabolism which was infeasible for HCM (29 FBA modes versus more than 153,000 elementary modes). Global sensitivity analysis further reduced the number of FBA modes required to describe the aerobic E. coli data, while maintaining model fit. Thus, HCM-FBA is a promising alternative to HCM for large networks where the generation of elementary modes is infeasible.
