Some problems in the usage of Gibbs free energy in biochemistry.

The usage of Gibbs free energy (G) in biochemistry is examined critically. The textbook formulation of the Second Law of Thermodynamics as applied to chemically-reacting systems is reviewed. Cognizance of the established theory and terminology of chemical thermodynamics leads to the conclusion that the symbol "delta G", as used in most biochemical calculations of free-energy change (e.g. in freeze-clamp study of steady-state metabolic processes), is erroneous. The instantaneous change, symbolized by the expression (delta G/delta xi) (with xi the degree of advancement of the reaction), is seen to be the correct form for describing the thermodynamic quality of the reactions of cell metabolism. Mathematical and graphical analysis of a sample reaction demonstrates the fundamental difference between delta G and (delta G/delta xi). Some problems in the application and interpretation of free-energy change in biochemical systems are reviewed: (1) Advances in protein dynamics have revealed the free-energy linkage properties of the enzyme molecule in binding/catalytic events of catalysis, demanding that we view the thermodynamics of elementary enzyme reactions with a finer eye. (2) The reality of metabolic microenvironments in vivo leads to equivocation in the significance of free-energy changes measured under macroscopic conditions in vitro. (3) The physicochemical character of reaction dynamics in the living cell may in some cases exceed the domain of validity of such thermodynamic state functions as Gibbs free energy.