title: Mechanism of triphosphate hydrolysis in aqueous solution: QM/MM simulations in water clusters.
abstract: The mechanism of the hydrolysis reaction of the unprotonated methyl triphosphate (MTP) ester in water clusters has been modeled. The effective fragment potential based quantum mechanical-molecular mechanical (QM/MM) approach has been applied in the simulations. It is shown that the minimum energy reaction path is consistent with an assumption of a two-step dissociative-type process similar to the case of the guanosine triphosphate (GTP) hydrolysis in the Ras-GAP protein complex (Grigorenko, B. L.; Nemukhin, A. V.; Topol, I. A.; Cachau, R. E.; Burt, S. K. Proteins: Struct., Funct., Bioinf. 2005, 60, 495). At the first stage, a unified action of environmental molecular groups and the catalytic water molecule leads to a substantial spatial separation of the gamma-phosphate group from the rest of the molecule. At the second stage, inorganic phosphate H2PO4- is formed from water and the metaphosphate anion PO3- through the chain of proton transfers along hydrogen bonds. The estimated activation barriers for MTP in aqueous solution at both stages (20 and 14 kcal/mol) are substantially higher than the corresponding barriers for the GTP hydrolysis in the protein.
authors.affiliation: Department of Chemistry, M. V. Lomonosov Moscow State University, Moscow, 119992, Russian Federation.
authors.forename: Bella L
authors.initials: BL
authors.lastname: Grigorenko
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Rogov
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Nemukhin
mesh_terms: D003198:Computer Simulation; D006860:Hydrogen Bonding; D006868:Hydrolysis; D008956:Models, Chemical; D008958:Models, Molecular; D009943:Organophosphorus Compounds / Q000737:chemistry*; D012996:Solutions / Q000737:chemistry; D014867:Water / Q000737:chemistry*
chemical_list: D009943:Organophosphorus Compounds; D012996:Solutions; D014867:Water