Predicting behavior of large-scale biochemical networks represents one of the greatest challenges of bioinformatics and computational biology. Computational tools for predicting fluxes in biochemical networks are applied in the fields of integrated and systems biology, bioinformatics, and genomics, and to aid in drug discovery and identification of potential drug targets. Approaches, such as flux balance analysis (FBA), that account for the known stoichiometry of the reaction network while avoiding implementation of detailed reaction kinetics are promising tools for the analysis of large complex networks. Here we introduce energy balance analysis (EBA)--the theory and methodology for enforcing the laws of thermodynamics in such simulations--making the results more physically realistic and revealing greater insight into the regulatory and control mechanisms operating in complex large-scale systems. We show that EBA eliminates thermodynamically infeasible results associated with FBA.

We introduce the basic concepts and develop a theory for nonequilibrium steady-state biochemical systems applicable to analyzing large-scale complex isothermal reaction networks. In terms of the stoichiometric matrix, we demonstrate both Kirchhoff's flux law R ' J ' ¼ 0 over a biochemical species, and potential law R ' l ' ¼ 0 over a reaction loop. They reflect mass and energy conservation, respectively. For each reaction, its steady-state flux J can be decomposed into forward and backward one-way fluxes J ¼ J + -J -, with chemical potential difference Dl ¼ RT ln(J -/J + ). The product -JDl gives the isothermal heat dissipation rate, which is necessarily non-negative according to the second law of thermodynamics. The stoichiometric network theory (SNT) embodies all of the relevant fundamental physics. Knowing J and Dl of a biochemical reaction, a conductance can be computed which directly reflects the level of gene expression for the particular enzyme. For sufficiently small flux a linear relationship between J and Dl can be established as the linear fluxforce relation in irreversible thermodynamics, analogous to Ohm's law in electrical circuits.

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