QM/MM Investigation of ATP Hydrolysis in Aqueous Solution

Abstract

Adenosine-5'-triphosphate (ATP) hydrolysis represents a most important reaction in biology. Despite extensive research efforts, the mechanism for ATP hydrolysis in aqueous solution still remains under debate. Previous theoretical studies often predefined reaction coordinates to characterize the mechanism for ATP hydrolysis in water with Mg(2+) by evaluating free energy profiles through these preassumed reaction paths. In the present work, a nudged elastic band method is applied to identify the minimum energy path calculated with a hybrid quantum mechanics and molecular mechanics approach. Along the reaction path, the free energy profile was obtained to have a single transition state and the activation energy of 32.5 kcal/mol. This transition state bears a four-centered structure that describes a concerted nature of the reaction. In the More-O'Ferrall-Jencks diagram, the results show that the reaction proceeds through a concerted path before the system reaches the transition state and along an associative path after the transition state. In addition, the calculated reaction free energy is -7.0 kcal/mol, in good agreement with experiment, capturing the exothermic feature of MgATP(2-) hydrolysis in aqueous solution, whereas the reaction was often shown to be endothermic in the previous theoretical studies. As Mg(2+) is required for ATP hydrolysis in cells, its role in the reaction is also elucidated.

The GTPase hGBP1 converts GTP to GMP in two steps via proton shuttle mechanisms

“…3(a) and (b), which is consistent with results obtained from previous computational studies on GTP/ATP/MeTP hydrolysis in bulk water. 29,31–34 The reactant minimum on the free energy landscape underlying the reference reaction, 1R , is represented by an intact MeTP, which is coordinated to the Mg 2+ ion by one of its γ- and one of its β-oxygens being both negatively charged, see Fig. 3.…”

“…The free energy barrier for MeTP hydrolysis in our reference bulk water solution of 33 kcal mol –1 is consistent with previous theoretical results for GTP/ATP/MeTP hydrolysis in bulk water. 29,31–34 This barrier only exceeds slightly that of the one-step process in the enzyme (26 kcal mol –1 ), whereas the rate-determining barrier of the two-step indirect SAC reaction is significantly lower (18 kcal mol –1 ) in hGBP1.…”

The effect of magnesium ions on triphosphate hydrolysis

“…Following from this, there have been a number of recent different computational studies of GTP, ATP and methyl triphosphate hydrolysis in aqueous solution [36][37][38][39][40][41][42][43], exploring preferred mechanistic options and, where metal ions have been included, the potential roles of the metal ion. Interestingly, some of these studies have provided quite contradictory mechanistic interpretations depending on the precise level of theory used and how the simulations were set up, making it hard to reach any concrete mechanistic conclusions.…”

Effects of protonation on the hydrolysis of triphosphate in vacuum and the implications for catalysis by nucleotide hydrolyzing enzymes

“…In all cases studied here, water W a is taken to transfer one of its protons to the nearest phosphate oxygen, namely of the γ-phosphate. This proton transfer mechanism is referred to as direct proton transfer [7, 46]. Reactant and product structures (see Fig.…”