Drastic Compensation of Electronic and Solvation Effects on ATP Hydrolysis Revealed through Large-Scale QM/MM Simulations Combined with a Theory of Solutions

Hydrolysis of adenosine triphosphate (ATP) is the “energy source” for a variety of biochemical processes. In the present work, we address key features of ATP hydrolysis: the relatively moderate value (about −10 kcal/mol) of the standard free energy, Δ<i>G</i>_hyd, of reaction and the insensitivity of Δ<i>G</i>_hyd to the number of excess electrons on ATP. We conducted quantum mechanical/molecular mechanical simulation combined with the energy-representation theory of solutions to analyze the electronic-state and solvation contributions to Δ<i>G</i>_hyd. It was revealed that the electronic-state contribution in Δ<i>G</i>_hyd is largely negative (favorable) upon hydrolysis, due to the reduction of electrostatic repulsion accompanying the breakage of the P–O bond. In contrast, the solvation effect was found to be strongly more favorable on the reactant side. Thus, we showed that a drastic compensation of the two opposite effects takes place, leading to the modest value of Δ<i>G</i>_hyd at each number of excess electrons examined. The computational analyses were also conducted for pyrophosphate ions (PPi), and the parallelism between the ATP and PPi hydrolyses was confirmed. Classical molecular dynamics simulation was further carried out to discuss the effect of the solvent environment; the insensitivity of Δ<i>G</i>_hyd to the number of excess electrons was seen to hold in solvent water and ethanol