Assessing structural uncertainty of biochemical regulatory networks in metabolic pathways under varying data quality.

ABSTRACT

Ordinary differential equation (ODE) models are powerful tools for studying the dynamics of metabolic pathways. However, key challenges lie in constructing ODE models for metabolic pathways, specifically in our limited knowledge about which metabolite levels control which reaction rates. Identification of these regulatory networks is further complicated by the limited availability of relevant data. Here, we assess the conditions under which it is feasible to accurately identify regulatory networks in metabolic pathways by computationally fitting candidate network models with biochemical systems theory (BST) kinetics to data of varying quality. We use network motifs commonly found in metabolic pathways as a simplified testbed. Key features correlated with the level of difficulty in identifying the correct regulatory network were identified, highlighting the impact of sampling rate, data noise, and data incompleteness on structural uncertainty. We found that for a simple branched network motif with an equal number of metabolites and fluxes, identification of the correct regulatory network can be largely achieved and is robust to missing one of the metabolite profiles. However, with a bi-substrate bi-product reaction or more fluxes than metabolites in the network motif, the identification becomes more challenging. Stronger regulatory interactions and higher metabolite concentrations were found to be correlated with less structural uncertainty. These results could aid efforts to predict whether the true metabolic regulatory network can be computationally identified for a given stoichiometric network topology and dataset quality, thus helping to identify optimal measures to mitigate such identifiability issues in kinetic model development.