The real reason why ATP hydrolysis is spontaneous at pH > 7: It's (mostly) the proton concentration!

Common wisdom holds that ATP hydrolysis is spontaneous because of the weakness of its phosphoanhydride bonds, electrostatic repulsion within the polyanionic ATP 4- molecule, and resonance stabilization of the inorganic phosphate and ADP products. By examining the pH-dependence of the hydrolysis Gibbs free energy, we show that in fact, above pH 7, ATP hydrolysis is spontaneous due mainly to the low concentration of the H + that is released as product. Hence, ATP is essentially just an electrophilic target whose attack by H 2 O causes the acidity of the water nucleophile to increase dramatically; the spontaneity of the resulting acid ionization supplies much of the released Gibbs free energy. We also find that fermentation lowers pH not due to its organic acid products (e.g., lactic, acetic, formic, or succinic acids), but again, due to the H + product of ATP hydrolysis.