Scalable computation of intracellular metabolite concentrations

TL;DR

This paper introduces scalable computational methods to estimate intracellular metabolite concentrations within constraint-based models, improving biological feasibility predictions by incorporating thermodynamic constraints efficiently.

Contribution

It presents novel polynomial optimization, random sampling, and global optimization techniques that leverage biophysical model structures for scalable intracellular metabolite concentration estimation.

Findings

Global optimization scales better for large networks

Methods provide feasible concentration sets within physiological ranges

Approaches outperform previous techniques in computational efficiency

Abstract

Current mathematical frameworks for predicting the flux state and macromolecular composition of the cell do not rely on thermodynamic constraints to determine the spontaneous direction of reactions. These predictions may be biologically infeasible as a result. Imposing thermodynamic constraints requires accurate estimations of intracellular metabolite concentrations. These concentrations are constrained within physiologically possible ranges to enable an organism to grow in extreme conditions and adapt to its environment. Here, we introduce tractable computational techniques to characterize intracellular metabolite concentrations within a constraint-based modeling framework. This model provides a feasible concentration set, which can generally be nonconvex and disconnected. We examine three approaches based on polynomial optimization, random sampling, and global optimization. We leverage the sparsity and algebraic structure of the underlying biophysical models to enhance the computational efficiency of these techniques. We then compare their performance in two case studies, showing that the global-optimization formulation exhibits more desirable scaling properties than the random-sampling and polynomial-optimization formulation, and, thus, is a promising candidate for handling large-scale metabolic networks.