Quantum and Classical Dynamics Simulations of ATP Hydrolysis in Solution

Harrison, Christopher B.; Schulten, Klaus

doi:10.1021/ct200886j

Cited by 45 publications

(68 citation statements)

References 60 publications

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“…In the previous study, 7,8 Mg 2+ is pentacoordinate at the PS. This undercoordination, which was attributed to that the solvent structure in the final configuration was not fully relaxed as pointed out by Akola and Jones, 7 can make a contribution to the positive reaction free energy in the previous calculations.…”

Section: Discussionmentioning

confidence: 78%

“…It has been not clear whether ATP hydrolysis in solution follows a reaction path between these two limits. In addition, the previous studies 7,8 showed that the reaction free energy of ATP hydrolysis in solution was endothermic, unfortunately failing to capture the exothermic feature of the reaction. 23 In the present work, the initial geometry of MgATP 2-is generated using the bond length and angle information from the references.…”

Section: Introductionmentioning

confidence: 97%

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QM/MM Investigation of ATP Hydrolysis in Aqueous Solution

2015

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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.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 97%

QM/MM Investigation of ATP Hydrolysis in Aqueous Solution

2015

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“…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.…”

Section: Introductionmentioning

confidence: 99%

The effect of magnesium ions on triphosphate hydrolysis

Barrozo

Blaha-Nelson

Williams

et al. 2017

Pure and Applied Chemistry

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Abstract:The role of metal ions in catalyzing phosphate ester hydrolysis has been the subject of much debate, both in terms of whether they change the transition state structure or mechanistic pathway. Understanding the impact of metal ions on these biologically critical reactions is central to improving our understanding of the role of metal ions in the numerous enzymes that facilitate them. In the present study, we have performed density functional theory studies of the mechanisms of methyl triphosphate and acetyl phosphate hydrolysis in aqueous solution to explore the competition between solvent-and substrate-assisted pathways, and examined the impact of Mg 2 + on the energetics and transition state geometries. In both cases, we observe a clear preference for a more dissociative solvent-assisted transition state, which is not significantly changed by coordination of Mg 2 + . The effect of Mg 2 + on the transition state geometries for the two pathways is minimal. While our calculations cannot rule out a substrate-assisted pathway as a possible solution for biological phosphate hydrolysis, they demonstrate that a significantly higher energy barrier needs to be overcome in the enzymatic reaction for this to be an energetically viable reaction pathway.

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“…Different computational studies of ATP hydrolysis indicate the dissociative mechanism energetically more favorable than the associative one. [17][18][19] Others show very small energetic difference between the associative, dissociative and concerted mechanisms. 20 And more recently, different QM/MM studies [21][22] of the ATP hydrolysis in myosin indicates the flexibility of the hydrolysis mechanism of this enzyme which presented similar free energies, and the dissociative mechanism like the most favorable within a metaphosphate compound.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Study of the Phosphoryl Transfer Reaction from ATP to Dha Catalyzed by DhaK from Escherichia coli

2017

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Protein kinases, representing one of the largest protein family involved in almost all aspects of cell life, have become one of the most important targets for the development of new drugs to be used in, for instance, cancer treatments. In this paper an exhaustive theoretical study of the phosphoryl transfer reaction from adenosine triphosphate (ATP) to dihydroxyacetone (Dha) catalyzed by DhaK from Escherichia coli (E. coli) is reported. Two different mechanisms, previously proposed for the phosphoryl transfer from ATP to the hydroxyl side chain of specific serine, threonine or tyrosine residues, have been explored based on the generation of free energy surfaces (FES) computed with hybrid QM/MM potentials. The results suggest that the substrate-assisted phosphoryl and proton-transfer mechanism is kinetically more favorable than the mechanism where an aspartate would be activating the Dha. Although the details of the mechanisms appear to be dramatically dependent on the level of theory employed in the calculations (PM3/MM, B3LYP:PM3/MM or B3LYP/MM), the transition states (TSs) for the phosphoryl transfer step appear to be described as a concerted step with different degrees of synchronicity in the breaking and forming bonds process in both explored mechanisms. Residues of the active site belonging to different subunits of the protein such as Gly78B, Thr79A, Ser80A, Arg178B and one Mg 2+ cation would be stabilizing the transferred phosphate in the TS. Asp109A would have a structural role by posing the Dha and other residues of the active site in the proper orientation. The information derived from our calculations not only reveals the role of the enzyme and the particular residues of its active site, but it can assist in the rationally design of new more specific inhibitors.3

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Quantum and Classical Dynamics Simulations of ATP Hydrolysis in Solution

Cited by 45 publications

References 60 publications

QM/MM Investigation of ATP Hydrolysis in Aqueous Solution

QM/MM Investigation of ATP Hydrolysis in Aqueous Solution

The effect of magnesium ions on triphosphate hydrolysis

Theoretical Study of the Phosphoryl Transfer Reaction from ATP to Dha Catalyzed by DhaK from Escherichia coli

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