Thermodynamic constraints in COBRA models can be refined. (a) For example, when a metabolic network is not adequately constrained, metabolites can cycle infinitely in loops. Akin to Kirchhoff’s loop law for electrical circuits, this property is thermodynamically infeasible. (b) Thus, methods like ll-FVA, which uses the loopless-COBRA96 constraints on flux variability analysis, are able to systematically remove these loops by adding a constraint that limits flux to the solution space regions that are not involved in these loops.