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Theoretical Studies of the Hydroxide-Catalyzed P−O Cleavage Reactions of Neutral Phosphate Triesters and Diesters in Aqueous Solution: Examination of the Changes Induced by H/Me Substitution
journal contribution
posted on 2005-12-01, 00:00 authored by Nathalie Iché-Tarrat, Jean-Claude Barthelat, Daniel Rinaldi, Alain VigrouxDFT calculations and dielectric continuum methods have been employed to map out the lowest activation
free-energy profiles for the alkaline hydrolysis of representative phosphate triesters and diesters, including
trimethyl phosphate (TMP), dimethyl 4-nitrophenyl phosphate (DMNPP), dimethyl hydrogen phosphate
(DMHP), and the dimethyl phosphate anion (DMP-). The reliability of the calculations is supported by the
excellent agreement observed between the calculated and the experimentally determined activation enthalpies
for phosphate triesters with poor (TMP) and good (DMNPP) leaving groups. The results obtained for the
OH- + DMHP and OH- + DMP- reactions are also consistent with all the available experimental information
concerning the hydrolysis reaction of dimethyl phosphate anion at pH > 5. By performing geometry
optimizations in the dielectric field (ε = 78.39), we found that OH- can attack the phosphorus atom of
DMHP without capturing its proton only if the O−H bond of DMHP is oriented opposite the attacking OH-
group. In these conditions, the rate for OH- attack on DMHP was found to be ∼103-fold faster than that for
OH- attack on TMP. The calculated rate acceleration induced by the phosphoryl proton corresponds to the
maximum rate effect expected from kinetic studies. Overall, our calculations performed on the dimethyl
phosphate ester predict that, contrary to what is generally observed for RNA and aryl phosphodiesters, the
water-promoted P−O cleavage reaction of DNA should dominate the base-catalyzed reaction at pH 7. These
results are suggestive that nucleases may be less proficient as catalysts than has recently been suspected.
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hydrolysis reactionDMHPrate accelerationdielectric continuum methodsOHtrimethyl phosphateDMPdimethyl phosphate anionTheoretical Studiesrate effectTMPactivation enthalpiesphosphoryl protonNeutral Phosphate TriestersDNADFTgeometry optimizationsphosphate triestersaryl phosphodiestersRNAdimethyl phosphate estercalculationDMNPPrepresentative phosphate triesterspH 7.Changes Inducedphosphorus atom
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