Free energy analyses for the ATP hydrolysis in aqueous solution by large-scale QM/MM simulations combined with a theory of solutions

Abstract

We conducted a set of molecular simulations referred to as QM/MM-ER, which combines a hybrid QM/MM with a theory of solutions, to elucidate the microscopic mechanism for the free energy release ΔGhyd associated with hydrolyses of ATP (adenosine triphosphate) or PPi (pyrophosphoric acid) in aqueous solutions. A particular interest is placed on an experimental fact that ΔGhyd stays almost constant irrespective of the number of excess charges on these solute molecules. In the QM/MM-ER simulations the free energy ΔGhyd was decomposed into the contributions ΔGele and ΔGsol which are, respectively, the free energies due to the electronic states and the solvations of the solutes. It was revealed that ΔGele is largely negative on the hydrolyses; that is, the products (ADP and Pi) are much stable in the electronic free energies than the reactants. This is attributed mostly to the reduction of the Coulomb repulsion among the excess electrons on ATP or PPi associated with the fragmentation. On the contrary, ΔGsol was found to be highly positive indicating the reactant states are much favorable for hydrations than the products, which can be qualitatively understood in terms of the Born's solvation model. Thus, a drastic compensation takes place between the two free energy contributions ΔGele and ΔGsol resulting in a modest free energy release ΔGhyd on hydrolyses. A set of classical molecular dynamics simulations for hydrolyses in ethanol was also performed to examine the effect of the dielectric constant of the solvent on the energetics. It was shown that the superb balance between ΔGele and ΔGsol established in water is seriously degraded in the ethanol solution.