Phosphate ester hydrolysis: calculation of gas-phase reaction paths and solvation effects

Dejaegere, Annick; Liang, Xiaoling; Karplus, Martin

doi:10.1039/ft9949001763

Cited by 70 publications

(104 citation statements)

References 41 publications

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“…Also, the barrier for phosphate diester hydrolysis in solution tends to be much lower than that obtained by such gas-phase studies. For instance, computational studies on the hydrolysis of dimethyl phosphate have obtained an activation free energy in the gas phase of 96 kcal mol x1 even though the experimental value in solution is significantly lower at 32 kcal mol x1 (Dejaegere et al 1994). Much more relevant information has been provided by a computational study (Rosta et al 2008) that mapped the full free-energy surface in solution and also took the activation entropy of the reaction into account for the hydrolysis of a series of homologous substituted methyl phenyl phosphate diesters.…”

Section: The Mechanism(s) Of Phosphate Diester Hydrolysismentioning

confidence: 99%

Why nature really chose phosphate

Kamerlin

Sharma

Prasad

et al. 2013

Quart. Rev. Biophys.

340

448

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Phosphoryl transfer plays key roles in signaling, energy transduction, protein synthesis, and maintaining the integrity of the genetic material. On the surface, it would appear to be a simple nucleophile displacement reaction. However, this simplicity is deceptive, as, even in aqueous solution, the low-lying d-orbitals on the phosphorus atom allow for eight distinct mechanistic possibilities, before even introducing the complexities of the enzyme catalyzed reactions. To further complicate matters, while powerful, traditional experimental techniques such as the use of linear free-energy relationships (LFER) or measuring isotope effects cannot make unique distinctions between different potential mechanisms. A quarter of a century has passed since Westheimer wrote his seminal review, ‘Why Nature Chose Phosphate’ (Science 235 (1987), 1173), and a lot has changed in the field since then. The present review revisits this biologically crucial issue, exploring both relevant enzymatic systems as well as the corresponding chemistry in aqueous solution, and demonstrating that the only way key questions in this field are likely to be resolved is through careful theoretical studies (which of course should be able to reproduce all relevant experimental data). Finally, we demonstrate that the reason that naturereallychose phosphate is due to interplay between two counteracting effects: on the one hand, phosphates are negatively charged and the resulting charge-charge repulsion with the attacking nucleophile contributes to the very high barrier for hydrolysis, making phosphate esters among the most inert compounds known. However, biology is not only about reducing the barrier to unfavorable chemical reactions. That is, the same charge-charge repulsion that makes phosphate ester hydrolysis so unfavorable also makes it possible to regulate, by exploiting the electrostatics. This means that phosphate ester hydrolysis can not only be turned on, but also be turned off, by fine tuning the electrostatic environment and the present review demonstrates numerous examples where this is the case. Without this capacity for regulation, it would be impossible to have for instance a signaling or metabolic cascade, where the action of each participant is determined by the fine-tuned activity of the previous piece in the production line. This makes phosphate esters the ideal compounds to facilitate life as we know it.

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Section: The Mechanism(s) Of Phosphate Diester Hydrolysismentioning

confidence: 99%

Why nature really chose phosphate

Kamerlin

Sharma

Prasad

et al. 2013

Quart. Rev. Biophys.

340

448

View full text Add to dashboard Cite

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“…2 (31); for water, the CHARMM modified TIP3 model (32) was used. Electrostatic interactions were decomposed into individual amino acid contributions as previously described (27,(33)(34)(35), and intermolecular interactions and desolvation contributions were separated. van der Waals' interactions between the ligand and LBD were computed with the CHARMM force field using a Lennard-Jones 6 -12 potential, (with a switching function between 8.5 and 12.5 Å for cutoff) and decomposed into individual amino acid contributions.…”

Section: Methodsmentioning

confidence: 99%

Critical Role of Desolvation in the Binding of 20-Hydroxyecdysone to the Ecdysone Receptor

Browning

Martin

Loch

et al. 2007

Journal of Biological Chemistry

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The insect steroid hormone 20-hydroxyecdysone (20E) binds to its cognate nuclear receptor composed of the ecdysone receptor (EcR) and Ultraspiracle (USP) and triggers the main developmental transitions, in particular molting and metamorphosis. We present the crystal structure of the ligand-binding domains of EcR/USP in complex with 20E at 2.4 Å resolution and compare it with published structures of EcR/USP bound to ponasterone A (ponA). ponA is essentially identical to 20E but lacks the 25-OH group of 20E. The structure of 20E-bound EcR indicates that an additional hydrogen bond is formed compared with the ponA-bound receptor, yet, paradoxically, ponA has a significantly higher affinity for EcR than 20E.

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“…As a result, phosphate esters have been the subject of extensive experimental 3,6-13 and theoretical [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] studies (though the precise mechanisms of both the solution and enzyme catalyzed reactions remain controversial, see e.g. [6][7][8]12,14,15,25,26,29,[33][34][35] ).…”

Section: Introductionmentioning

confidence: 99%

Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

Kamerlin

2011

J. Org. Chem.

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Both phosphoryl and sulfuryl transfer are ubiquitous in biology, being involved in a wide range of processes, ranging from cell division to apoptosis. Additionally, it is becoming increasingly clear that enzymes that can catalyze phosphoryl transfer can often cross-catalyze sulfuryl-transfer (and vice versa).However, while there have been extensive experimental and theoretical studies performed on phosphoryl transfer, the body of available research on sulfuryl transfer is comparatively much smaller.The present work presents a direct theoretical comparison of p-nitrophenyl phosphate and sulfate monoester hydrolysis, both of which are considered prototype systems for probing phosphoryl and sulfuryl transfer respectively. Specifically, free energy surfaces have been generated using density functional theory, by initial geometry optimization in PCM using the 6-31+G* basis set and the B3LYP density functional, followed by single point calculations using the larger 6-311+G** basis set and the COSMO continuum model. The resulting surfaces have been then used to identify the relevant transition states, either by further unconstrained geometry optimization, or from the surface itself where possible.Additionally, configurational entropies were evaluated using a combination of the quasiharmonic approximation and the restraint release approach and added to the calculated activation barriers as a correction. Finally, the overall activation entropy was estimated by approximating the solvent contribution to the total activation entropy using the Langevin dipoles solvation model. We have reproduced both the experimentally observed activation barriers and the observed trend in the activation entropies with reasonable accuracy, as well providing a comparison of calculated and observed 15 N and 18 O kinetic isotope effects. We demonstrate that, counterintuitively, the hydrolysis of the p-nitrophenyl sulfate proceeds through a more expa show that the solvation effects upon moving from the ground state to the transition state are quite different for both reactions, suggesting that the enzymes that catalyze these reactions would need active 4 sites with quite different electrostatic preorganization for the efficient catalysis of either reaction (despite which many enzymes can catalyze both phosphoryl and sulfuryl transfer). We believe that such a comparative study is an important foundation for understanding the molecular basis for phosphatesulfate cross promiscuity within members of the alkaline phosphatase superfamily.

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Phosphate ester hydrolysis: calculation of gas-phase reaction paths and solvation effects

Cited by 70 publications

References 41 publications

Why nature really chose phosphate

Why nature really chose phosphate

Critical Role of Desolvation in the Binding of 20-Hydroxyecdysone to the Ecdysone Receptor

Theoretical Comparison ofp-Nitrophenyl Phosphate and Sulfate Hydrolysis in Aqueous Solution: Implications for Enzyme-Catalyzed Sulfuryl Transfer

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