Atomic‐resolution dissection of the energetics and mechanism of isomerization of hydrated ATP‐Mg²⁺ through the SOMA string method

Abstract

The atomic mechanisms of isomerization of ATP-Mg(2+) in solution are characterized using the recently developed String Method with Optimal Molecular Alignment (SOMA) and molecular-dynamics simulations. Bias-Exchange Metadynamics simulations are first performed to identify the primary conformers of the ATP-Mg(2+) complex and their connectivity. SOMA is then used to elucidate the minimum free-energy path (MFEP) for each transition, in a 48-dimensional space. Analysis of the per-atom contributions to the global free-energy profiles reveals that the mechanism of these transitions is controlled by the Mg(2+) ion and its coordinating oxygen atoms in the triphosphate moiety, as well as by the ion-hydration shell. Metadynamics simulations in path collective variables based on the MFEP demonstrate these isomerizations proceed across a narrow channel of configurational space, thus validating the premise underlying SOMA. This study provides a roadmap for the examination of conformational changes in biomolecules, based on complementary enhanced-sampling techniques with different strengths. © 2015 Wiley Periodicals, Inc.

ATP dependent NS3 helicase interaction with RNA: insights from molecular simulations

“…On the contrary, the open-ATP structure ex-periences a reorganization of the binding pocket after 2 nanoseconds. In particular, a bending of the ATP is observed which leads to the coordination of the Mg 2+ cation to α, β and γ phosphates, which corresponds to an alternative metastable conformation of the ATP/Mg 2+ complex [63]. Moreover, a contact between Mg 2+ and D290 (DExH box) is formed and the contact between Mg 2+ and S211 is now mediated by a water molecule.…”

Molecular mechanisms of human P2X3 receptor channel activation and modulation by divalent cation bound ATP

“…The prevalent geometries are instead those in which Mg 2+ is coordinated by both the β- and γ-phosphates or by all three phosphate groups concurrently. These two interaction modes are also the most energetically favorable when Mg 2+ -ATP is in solution (Branduardi et al, 2016). That the Mg 2+ -ATP complex observed in our structures adopts a rare configuration suggests that interactions between the receptor and divalent ions have a dominant effect in determining the structure and stability of the complex.…”

“…From the available structure of hP2X3 bound by free-ATP, it is unclear how the receptor might accommodate a divalent-bound nucleotide. When ATP is in solution, the divalent ion preferably interacts with the β− and γ−phosphate groups simultaneously, or alternatively, with all three phosphate groups (Branduardi et al, 2016; Cohn and Hughes, 1962). Whether these interactions are compatible with those observed between free ATP and the receptor in the ATP-bound structure is unclear; even if they are, the presence of divalent ions would effectively weaken the interaction between agonist and receptor, which would be physiologically counterintuitive.…”

ATP Can Efficiently Stabilize Protein through a Unique Mechanism

“…In most of the trajectory, ATP–Mg complexes adopted the coordination mode that Mg 2+ simultaneously binds to two phosphates (i.e., β-P and γ-P) of the same ATP ( Figure S1 ), in agreement with previous simulation results. 63 − 66 Such a conformation was then adopted for the following simulations.…”