Thermodynamics of Chemical Reactions in Open Systems Reduced by PEA and QSSA

Abstract: Previous studies have primarily focused on the nonequilibrium thermodynamics of chemical reaction networks (CRNs) occurring in closed systems. In contrast, CRNs in open systems exhibit much richer nonequilibrium phenomena due to sustained matter and energy exchange. Here, we bridge the quantitative relationships between essential thermodynamic quantities -- including the steady state, enthalpy, intrinsic Gibbs free energy, and entropy production rate -- in original mass-action equations and their PEA- or QSSA-reduced counterparts for open CRNs. Our analysis demonstrates that the thermodynamic structure, especially the second law of thermodynamics, of the full CRNs may not be preserved in reduced models when algebraic relations are imposed. Specifically, PEA-reduced models lose monotonicity in the intrinsic Gibbs free energy, whereas QSSA retains this property. These theoretical findings are further validated through analytical and numerical studies of two archetypal open systems: the Michaelis-Menten reactions and the phosphorylation-dephosphorylation cycle (PdPC). Our results provide a systematic framework for evaluating the fidelity of reduced models.