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Effective Dynamic Models of Metabolic Networks Michael Vilkhovoy∗, Mason Minot∗, Jeffrey D

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Effective Dynamic Models of Metabolic Networks Michael Vilkhovoy∗, Mason Minot∗, Jeffrey D bioRxiv preprint doi: https://doi.org/10.1101/047316; this version posted August 31, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Effective Dynamic Models of Metabolic Networks Michael Vilkhovoy∗, Mason Minot∗, Jeffrey D. Varner∗ ∗School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14850 USA Abstract—Mathematical models of biochemical networks are by a pseudo enzyme whose expression is controlled by an useful tools to understand and ultimately predict how cells utilize optimal decision) to achieve a physiological objective (Fig. nutrients to produce valuable products. Hybrid cybernetic models 1A). HCMs generate intracellular flux distributions consistent in combination with elementary modes (HCM) is a tool to model cellular metabolism. However, HCM is limited to reduced with other approaches such as metabolic flux analysis (MFA), metabolic networks because of the computational burden of and also describe dynamic extracellular measurements superior calculating elementary modes. In this study, we developed the to dynamic FBA (DFBA) [12]. However, HCMs are restricted hybrid cybernetic modeling with flux balance analysis or HCM- to networks which can be decomposed into EMs (or EPs). FBA technique which uses flux balance solutions instead of In this study, we developed the hybrid cybernetic modeling elementary modes to dynamically model metabolism. We show HCM-FBA has comparable performance to HCM for a proof with flux balance analysis (HCM-FBA) technique. HCM- of concept metabolic network and for a reduced anaerobic E. FBA is a modification of the hybrid cybernetic approach coli network. Next, HCM-FBA was applied to a larger metabolic of Ramkrishna and coworkers [12] which uses FBA solu- network of aerobic E. coli metabolism which was infeasible for tions (instead of EMs) in conjunction with cybernetic control HCM (29 FBA modes versus more than 153,000 elementary variables to dynamically simulate metabolism. Since HCM modes). Global sensitivity analysis further reduced the number of FBA modes required to describe the aerobic E. coli data, showed superior performance to DFBA, we compared the per- while maintaining model fit. Thus, HCM-FBA is a promising formance of HCM-FBA to HCM for a prototypical metabolic alternative to HCM for large networks where the generation of network, along with two real-world E. coli applications. HCM- elementary modes is infeasible. FBA performed comparably to HCM for the prototypical Index Terms—Metabolic models, flux balance analysis, cyber- network and a reduced anaerobic E. coli network, despite netic models having fewer parameters in each case. Next, HCM-FBA was applied to an aerobic E. coli metabolic network that was I. INTRODUCTION infeasible for HCM. HCM-FBA described cellmass growth Biotechnology harnesses the power of metabolism to pro- and the shift from glucose to acetate consumption with only duce products that benefit society. Constraints based models a few modes. Global sensitivity analysis allowed us to further E. coli are important tools to understand and ultimately to predict reduce the aerobic HCM-FBA model to the minimal how cells utilize nutrients to produce products. Constraints model required to describe the data. Thus, HCM-FBA is a based methods such as flux balance analysis (FBA) [1] and promising approach for the development of reduced order network decomposition approaches such as elementary modes dynamic metabolic models and a viable alternative to HCM (EMs) [2] or extreme pathways (EPs) [3] model intracellular or DFBA, especially for large networks where the generation metabolism using the biochemical stoichiometry and other of EMs is infeasible. constraints such as thermodynamical feasibility under pseudo- steady state conditions. FBA has been used to efficiently II. RESULTS estimate the performance of metabolic networks of arbitrary HCM-FBA was equivalent to HCM for a prototypical complexity, including genome scale networks, using linear metabolic network (Fig. 1). The proof of concept network, programming [4]. On the other hand, EMs (or EPs) catalog consisting of 6 metabolites and 7 reactions (Fig. 1B), generated all possible metabolic behaviors such that any flux distribution 3 FBA modes and 6 EMs. Using the EMs and synthetic predicted by FBA is a convex combination of the EMs parameters, we generated test data from which we estimated (or EPs) [5]. However, the calculation of EMs (or EPs) is the HCM-FBA model parameters. The best fit HCM-FBA computationally expensive and currently infeasible for genome model replicated the synthetic data (Fig. 1C). The HCM and scale networks [6]. HCM-FBA kinetic parameters were not quantitatively identi- Cybernetic models are an alternative to the constraints based cal, but had similar orders of magnitude; the FBA approach approach which hypothesize that metabolic control is the out- had 3 fewer modes, thus identical parameter values were not put of an optimal decision. Cybernetic models have predicted expected. The HCM-FBA approach replicated synthetic data mutant behavior [7, 8], steady-state multiplicity [9], strain spe- generated by HCM, despite having 3 fewer modes. Thus, we cific metabolism [10], and have been used in bioprocess con- expect HCM-FBA will perform similarly to HCM, despite trol applications [11]. Hybrid cybernetic models (HCM) have having fewer parameters. Next, we tested the ability of HCM- addressed earlier shortcomings of the approach by integrating FBA to replicate real-world experimental data. cybernetic optimality concepts with EMs. HCMs dynamically The performance of HCM-FBA was equivalent to HCM for choose combinations of biochemical modes (each catalyzed anaerobic E. coli metabolism (Fig. 2A). We constructed an Corresponding author: J. Varner (email:[email protected]). anaerobic E. coli network [12], consisting of 12 reactions and bioRxiv preprint doi: https://doi.org/10.1101/047316; this version posted August 31, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under 2 aCC-BY 4.0 International license. A A 1.0 B 1.0 Network HCM-EM HCM-FBA HCM FBA HCM FBA HCM EM Minor modes removed Data Major mode removed Data 0.5 Biomass (gDW/L) 0.5 Lactate (mM) Abundance Biomass (gDW/L) A Extracellular Biomass (gDW/L) Intracellular 0.0 0.0 A e Be 0 2 4 6 8 0 2 4 6 8 10 v4 v2 v3 30 C Glucose 12 Each mode Intracellular All possible modes Modes are combined by FBA considered separatelycellmass q3 precursor 20 8 Ce B B C Formate A Extracellular 10 4 Intracellular Glucose (mM) A Glucose (mM) Abundance (mM) q1 v1 q2 Abundance (mM) A A B e Be C v4 0 0 v2 v3 0 2 4 6 8 0 2 4 6 8 10 C Biomass 6 Abundance (A.U.) 40 Intracellular 20 cellmass q3 precursor 30 B 15 Acetate 4 Ce B Time (hr) 10 Ethanol 20 Succinate 2 Acetate (mM) 5 10 Acetate (mM) Abundance (mM) Fig. 1. HCMA proof of concept metabolic study. A: HCMs distribute uptake Abundance (mM) 0 0 0 and secretion fluxes amongst differentC pathways. For HCM, these pathways are 0 2 4 6 8 0 2 4 6 8 10 elementary modes; for HCM-FBA these are flux balance analysis solutions. TimeTime (hr)(hr) TimeTime (hr) (hr) HCM combines all possible modesBiomass within a network; whereas HCM-FBA combinesAbundance (A.U.) only steady-state paths estimated by flux balance analysis. B: Fig. 2. HCM-FBA versus HCM performance for small and large metabolic Prototypical network with six metabolites and seven reactions. Intracellular networks. A: Batch anaerobic E. coli fermentation data versus HCM-FBA cellmass precursors A; B, and C areB balanced (no accumulation) while the (solid) and HCM (dashed). The experimental data was reproduced from Kim extracellular metabolites (Ae;Be, and Ce) are not balanced (can accumulate). et al. [12]. Error bars represent the 90% confidence interval. B: Batch aerobic The oval denotes theTime cell (hr) boundary, qj is the jth flux across the boundary, E. coli fermentation data versus HCM-FBA (solid). Model performance is and vk denotes the kth intracellular flux. C: Simulation of extracellular also shown when minor modes (dashed) and major modes (dotted) were metabolite trajectories using HCM-FBA (solid line) versus HCM (points) for removed from the HCM-FBA model. The experimental data was reproduced the prototypical network. from Varma & Palsson [13]. Error bars denote a 10% coefficient of variation. 19 metabolites, which generated 7 FBA modes and 9 EMs. tivity coefficients were calculated for all kinetic parameters HCM reproduced cellmass, glucose, and byproduct trajectories and enzyme initial conditions in the aerobic E. coli model. using the kinetic parameters reported by Kim et al. [12] (Fig. Five of the 29 FBA modes were significant; removal of the 2A, points versus dashed). HCM-FBA model parameters were most significant of these modes (encoding aerobic growth estimated in this study from the Kim et al. data set using sim- on glucose) destroyed model performance (Fig. 2B, dotted). ulated annealing. Overall, HCM-FBA performed within 5% of Conversely, removing the remaining 24 modes simultaneously HCM (on a residual standard error basis) for the anaerobic E. had a negligible effect upon model performance (Fig. 2B, coli data (Fig. 2A, solid), despite having 2 fewer modes and dashed). The sensitivity analysis identified the minimal model 4 fewer parameters (17 versus 21 parameters). Thus, while structure required to explain the experimental data. both HCM and HCM-FBA described the experimental data, HCM-FBA did so with fewer modes and parameters. III. DISCUSSION HCM-FBA captured the shift from glucose to acetate con- sumption for a model of aerobic E.
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