title: 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.
abstract: DFT 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 (epsilon = 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 approximately 10(3)-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.
authors.affiliation: Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, UMR 5068 CNRS,, 31062 Toulouse Cedex 9, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Iché-Tarrat
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Barthelat
authors.forename: Daniel
authors.initials: D
authors.lastname: Rinaldi
authors.forename: Alain
authors.initials: A
authors.lastname: Vigroux
mesh_terms: D002384:Catalysis; D003198:Computer Simulation; D006868:Hydrolysis; D006878:Hydroxides / Q000737:chemistry*; D008956:Models, Chemical; D015394:Molecular Structure; D010755:Organophosphates / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry; D010758:Phosphorus / Q000737:chemistry; D012996:Solutions / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D006878:Hydroxides; D010755:Organophosphates; D012996:Solutions; D014867:Water; D010758:Phosphorus; C031356:hydroxide ion; D010100:Oxygen