Quantum mechanical calculations on phosphate hydrolysis reactions

Mercero, José M.; Barrett, Peter; Lam, Cheuk W.; Fowler, Joseph E.; Ugalde, Jesús M.; Pedersen, Lee G.

doi:10.1002/(sici)1096-987x(20000115)21:1<43::aid-jcc5>3.0.co;2-8

Cited by 36 publications

(49 citation statements)

References 16 publications

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“…The gas‐phase hydroxide attack on EP − requires a high energy for activation (Δ E

^{TS1^{−2}}

=85.0 kcal/mol). This reaction and its acyclic counterpart (OH − attack on DMP − ) have been well described in previous theoretical work 4–7, 12, and our results do not differ significantly from these conclusions. The origin of the high barrier is the coulombic repulsion for the approach of two anions (OH − and EP − ) in the gas phase.…”

Section: Resultssupporting

confidence: 92%

“…Phosphate diesters play a fundamental role in biology since they are the chemical group that link nucleotides in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) 1. The chemical properties and reactivity of phosphates determine how they are formed and cleaved, and therefore, phosphate diesters have been the subject of numerous theoretical and experimental studies 2–12. A particular case that has received much attention is the cleavage of RNA 13–17, through the hydrolysis of its phosphate diester linkage.…”

Section: Introductionmentioning

confidence: 99%

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Theoretical studies on the hydrolysis of phosphate diesters in the gas phase, solution, and RNase A

López

York

Dejaegere

et al. 2001

Int J of Quantum Chemistry

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Density functional theory, polarizable continuum models and semiempirical hybrid quantum mechanical/molecular mechanical (QM/MM) calculations were applied to the hydrolysis of phosphate diesters in the gas phase, in solution, and in the enzyme RNase A. Neutralization of the negative charge of the pentacovalent phosphorane intermediates provides a substantial stabilization of the transition-state structures in the gas phase. Inclusion of solvent effects on the phosphate/phosphorane species was critical to reproducing the trends in reactivity observed experimentally. Finally, the catalytic mechanism for the hydrolysis of uridine 2 ,3 -cyclic phosphate by RNase A was studied by QM/MM calculations. Our results suggest that the rate-limiting transition state of the reaction corresponds to the approach of a water molecule to the phosphate and its activation by His119. Thus, His119 acts as a generalized base for the reaction. The water attack leads to a pentacovalent phosphorane transition state of formal charge −2; this excess of negative charge in the transition state is stabilized by a number of positively charged residues including His12 and Lys41. In the second stage of the reaction, the phosphorane is converted into products. This part of the reaction proceeds without a detectable barrier, and it is facilitated by a proton transfer from Lys41 to the departing O 2 .

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“…The gas‐phase hydroxide attack on EP − requires a high energy for activation (Δ E

^{TS1^{−2}}

Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Theoretical studies on the hydrolysis of phosphate diesters in the gas phase, solution, and RNase A

López

York

Dejaegere

et al. 2001

Int J of Quantum Chemistry

View full text Add to dashboard Cite

show abstract

“…Disregarding, the reprotonation step, the remaining barrier of ∼19 kcal/mol for the energetically most favorable mechanism is comparable to rates of seconds to minutes as reported for several DNA cleaving enzymes [50,[71][72][73][74][75]. It is significantly lower than uncatalyzed phosphate hydrolysis [15] and also lower than the phosphate hydrolysis by the direct attack of a hydroxide ion on a phospho-diester [76].…”

Section: Dissociation Of the Scissile Bond In The Pentacovalent Intersupporting

confidence: 59%

Phosphodiester hydrolysis computed for cluster models of enzymatic active sites

Batebi

Imhof

2016

Theor Chem Acc

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Computation of phosphodiester hydrolysis in different models with one or two metal ions, representing typical active site architectures of nucleases, reveal an associative mechanism to be favorable in all of the cases studied in this work. Direct attack of the nucleophilic water molecule with proton transfer to the phosphate group is facilitated by an extra positive charge as provided by a metal ion located at the attack site or a positively charged histidine residue whereas no such contribution can be observed on leaving group departure. A major catalytic effect is found by proton transfer from the nucleophilic water molecule to a histidine-aspartate cluster. Attack of the thus generated hydroxide ion on the phosphate group is just sufficiently stabilized by the metal ions to allow subsequent P-O bond dissociation.

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“…Many studies, both theoretical and experimental, have been performed on phosphate esters because of their biological importance. Some examples are: methyl phosphate (MP 2− )1—a model molecule for serine and threonine phosphate which are fundamental in cell signaling; dimethyl phosphate (DMP − )2–4—a model molecule for the phosphodiester linkage in nucleic acids; and acetyl phosphate (AcP 2− )5—a model molecule for aspartyl phosphate which is present in P‐type ATPases.…”

Section: Introductionmentioning

confidence: 99%

Basis set dependence of phosphate frequencies in density functional theory calculations

Rudbeck

2011

Int J of Quantum Chemistry

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The addition of extravalence, polarization and diffuse functions, were studied in order to conclude how they affect the PAO stretching frequencies of several biological relevant phosphate molecules. The results show that the polarization and the diffuse functions have opposite effects on the frequencies: the polarization functions downshift while the diffuse functions upshift the frequencies. The effect of the valence functions was more difficult to interpret. The effect of the conductor-like screening model (CPCM)-continuum model was also studied. The results show that the CPCM-continuum model has a substantial effect on the frequencies for these small molecules. The continuum model's efficiency is mainly due to its effect on the geometries and not on the frequencies.

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Quantum mechanical calculations on phosphate hydrolysis reactions

Cited by 36 publications

References 16 publications

Theoretical studies on the hydrolysis of phosphate diesters in the gas phase, solution, and RNase A

Theoretical studies on the hydrolysis of phosphate diesters in the gas phase, solution, and RNase A

Phosphodiester hydrolysis computed for cluster models of enzymatic active sites

Basis set dependence of phosphate frequencies in density functional theory calculations

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