Ab initio dynamics of gas-phase and aqueous-phase hydrolysis of adenosine triphosphate

In this study, we have modelled the non-enzymatic hydrolysis of ATP in the gas-phase and the aqueous-phase by performing ab initio molecular dynamics simulations combined with an enhanced sampling technique. In the gas-phase, we studied hydrolysis of fully protonated ATP molecule, and in the aqueous-phase, we studied hydrolysis of ATP coordinated with: a) two H+ ions (H-ATP), b) Mg2+ (Mg-ATP), and c) Ca2+ (Ca-ATP). We show that gas-phase ATP hydrolysis follows a two-step dissociative mechanism via a highly stable metaphosphate intermediate. The Adenine group of the ATP molecule plays a crucial role of a general base; temporarily accepting protons and thus helping in the elimination-addition process. In the aqueous-phase hydrolysis of ATP, we find that the cage of solvent molecules increases the stability of the terminal phospho-anhydride bond through a well-known cage-effect. The nature of the ions has an important effect on the mechanism of the reaction. We find a two-step dissociative-type mechanism for H-ATP, a single-step dissociative-type mechanism for Mg-ATP, and an S-N-2 type concerted hydrolysis pathway for Ca-ATP.