title: The Competing Mechanisms of Phosphate Monoester Dianion Hydrolysis.
abstract: Despite the numerous experimental and theoretical studies on phosphate monoester hydrolysis, significant questions remain concerning the mechanistic details of these biologically critical reactions. In the present work we construct a linear free energy relationship for phosphate monoester hydrolysis to explore the effect of modulating leaving group pKa on the competition between solvent- and substrate-assisted pathways for the hydrolysis of these compounds. Through detailed comparative electronic-structure studies of methyl phosphate and a series of substituted aryl phosphate monoesters, we demonstrate that the preferred mechanism is dependent on the nature of the leaving group. For good leaving groups, a strong preference is observed for a more dissociative solvent-assisted pathway. However, the energy difference between the two pathways gradually reduces as the leaving group pKa increases and creates mechanistic ambiguity for reactions involving relatively poor alkoxy leaving groups. Our calculations show that the transition-state structures vary smoothly across the range of pKas studied and that the pathways remain discrete mechanistic alternatives. Therefore, while not impossible, a biological catalyst would have to surmount a significantly higher activation barrier to facilitate a substrate-assisted pathway than for the solvent-assisted pathway when phosphate is bonded to good leaving groups. For poor leaving groups, this intrinsic preference disappears.
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University , BMC Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Duarte
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University , BMC Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Barrozo
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University , BMC Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Åqvist
authors.affiliation: Department of Chemistry, Sheffield University , Sheffield S3 7HF, United Kingdom.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Williams
authors.affiliation: Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University , BMC Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Shina C L
authors.initials: SC
authors.lastname: Kamerlin