ATP Hydrolysis in Water − A Density Functional Study

Abstract

Adenosine 5′-triphosphate (ATP) is a basic energy carrier in cellular metabolism. As a high-energy intermediate, it provides a way to convert energy from one biochemical process to another via an environment-dependent hydrolysis reaction. Two paths for ATP hydrolysis in water with Mg 2+ are studied here using the density functional method: an associative reaction involving a nucleophilic attack of one water molecule, and a dissociative reaction involving a scission of the terminal bridging P-O bond. The latter has an activation energy of 35 kcal/mol, where 25 kcal/mol can be assigned to the P-O bond breaking and 10 kcal/mol to the artificial stability of PO 3 -resulting from the small size and the short time scale of the simulation. The path and energy barrier (39 kcal/mol) of the less-favorable associative reaction suggest that it is possible only under conditions where the lytic water is already deprotonated to OH -. The Mg cation elongates the terminal bridging P-O bond when forming a bidentate chelate with the two terminal phosphates. Additional constrained displacements of Mg 2+ with respect to the nearest phosphate oxygens show that a direct electrophilic attack of Mg toward a bridging O is possible.

Why nature really chose phosphate

“…Subsequent studies by the same authors (Akola & Jones, 2003) tried to explore ATP hydrolysis in actin using MD simulations with an MM force field to generate starting points for cluster modeling. In this case, a perfectly valid S N 2 TS is called ' dissociative ', and a reaction where another water serves as a base is defined as an ' associative ' mechanism (the same problem mentioned in Section 3.5).…”

“…In fact, resolving the central controversies is not helped by the problematic tendency (e.g. Akola & Jones, 2003 ;Grigorenko et al 2007a ;Smith et al 2011) to call perfect associative or S N 2 pathways ' dissociative ', or to describe a system where the distance between central phosphorus atom and the oxygen atom of the attacking nucleophile is 1Á8 Å as involving a ' metaphosphate ' species (Grigorenko et al 2006). Nevertheless, we are encouraged to see that, in addition to systematic works using implicit solvent models, the QM/MM community is also starting to get reasonable results for phosphate hydrolysis in solution (Wenjin et al 2012), which incidentally reproduces our results using an implicit solvent (Kamerlin et al 2008a ;Klähn et al 2006).…”

Quantitative exploration of the molecular origin of the activation of GTPase

“…That is, in addition to uncritical theoretical studies of phosphate hydrolysis by irrelevant gas phase and energy minimization studies (for discussion see ref. 11), even recent studies that involve some configurational sampling (12,13), or path search approaches (14) (see Exploring the Activation of EF-Tu and SI Text), have not provided yet reliable mechanistic picture. The difficulty to elucidate the mechanism reflected several problems including the most studies have not explored all of the possible options (including key earlier proposals).…”

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.…”