RESUMO
Integrated modeling of metabolism and gene regulation continues to be a major challenge in computational biology. While there exist approaches like regulatory flux balance analysis (rFBA), dynamic flux balance analysis (dFBA), resource balance analysis (RBA) or dynamic enzyme-cost flux balance analysis (deFBA) extending classical flux balance analysis (FBA) in various directions, there have been no constraint-based methods so far that allow predicting the dynamics of metabolism taking into account both macromolecule production costs and regulatory events. In this paper, we introduce a new constraint-based modeling framework named regulatory dynamic enzyme-cost flux balance analysis (r-deFBA), which unifies dynamic modeling of metabolism, cellular resource allocation and transcriptional regulation in a hybrid discrete-continuous setting. With r-deFBA, we can predict discrete regulatory states together with the continuous dynamics of reaction fluxes, external substrates, enzymes, and regulatory proteins needed to achieve a cellular objective such as maximizing biomass over a time interval. The dynamic optimization problem underlying r-deFBA can be reformulated as a mixed-integer linear optimization problem, for which there exist efficient solvers.
Assuntos
Redes e Vias Metabólicas , Modelos Biológicos , Biomassa , Regulação da Expressão Gênica , Análise do Fluxo MetabólicoRESUMO
The computational analysis of phototrophic growth using constraint-based optimization requires to go beyond current time-invariant implementations of flux-balance analysis (FBA). Phototrophic organisms, such as cyanobacteria, rely on harvesting the sun's energy for the conversion of atmospheric CO2 into organic carbon, hence their metabolism follows a strongly diurnal lifestyle. We describe the growth of cyanobacteria in a periodic environment using a new method called conditional FBA. Our approach enables us to incorporate the temporal organization and conditional dependencies into a constraint-based description of phototrophic metabolism. Specifically, we take into account that cellular processes require resources that are themselves products of metabolism. Phototrophic growth can therefore be formulated as a time-dependent linear optimization problem, such that optimal growth requires a differential allocation of resources during different times of the day. Conditional FBA then allows us to simulate phototrophic growth of an average cell in an environment with varying light intensity, resulting in dynamic time-courses for all involved reaction fluxes, as well as changes in biomass composition over a diurnal cycle. Our results are in good agreement with several known facts about the temporal organization of phototrophic growth and have implications for further analysis of resource allocation problems in phototrophic metabolism.