title: Exploring the Multidimensional Free Energy Surface of Phosphoester Hydrolysis with Constrained QM/MM Dynamics.
abstract: The mechanism of the hydrolysis of phosphate monoesters, a ubiquitous biological reaction, has remained under debate. We here investigated the hydrolysis of a nonenzymatic model system, the monomethyl phosphate dianion, by hybrid quantum mechanical and molecular mechanical simulations. The solvation effects were taken into account with explicit water. Detailed free energy landscapes in two-dimensional and three-dimensional space were resolved using the multidimensional potential of mean constraint force, a newly developed method that was demonstrated to be powerful for free energy calculations along multiple coordinates. As in previous theoretical studies, the associative and dissociative pathways were indistinguishable. Furthermore, the associative pathway was investigated in great detail. We propose a rotation of an O-H bond in the transition between two pentacoordinated structures, during which an overall transition state was identified with an activation energy of 50 kcal/mol. This is consistent with experimental data. The results support a concerted proton transfer from the nucleophilic water to the phosphate group, and then to the leaving group.
authors.affiliation: CAS-MPG Partner Institute and Key Laboratory for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.|Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany.
authors.forename: Wenjin
authors.initials: W
authors.lastname: Li
authors.affiliation: Ruhr-Universität Bochum, Lehrstuhl für Biophysik ND 04, 44780 Bochum, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Rudack
authors.affiliation: CAS-MPG Partner Institute and Key Laboratory for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.|Ruhr-Universität Bochum, Lehrstuhl für Biophysik ND 04, 44780 Bochum, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Gerwert
authors.affiliation: CAS-MPG Partner Institute and Key Laboratory for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.|Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Gräter
authors.affiliation: Ruhr-Universität Bochum, Lehrstuhl für Biophysik ND 04, 44780 Bochum, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schlitter