Accessible Gibbs energy at metabolic activation limits long-term cell growth

When exposed to a nutrient, cells activate metabolism by reorganizing metabolite pools and enzyme expression to approach the maximal growth rate permitted by physicochemical constraints. While these constraints define reachable steady states, here we propose that the Gibbs energy accessible at activation further limits which states are reached. Using minimal metabolic models, we find that limited accessible Gibbs energy can trap cells in low-growth states by constraining metabolic reorganization and imposing a proteomic burden on transport and phosphorylation reactions. To investigate this experimentally, we reconstituted the arginine deiminase pathway in vesicles, revealing that the size of a conserved pool of interconverting metabolites (arginine, citrulline, and ornithine) determines accessible Gibbs energy and constrains steady-state ATP production rate, a proxy for growth. Together, these results indicate that cellular metabolism retains memory of its initial energetic state, with accessible Gibbs energy at activation acting as a thermodynamic constraint on long-term growth.