Density functional theory (DFT) calculations were used to explore the hydrolysis mechanism of the DNA analog BNPP (BNPP= bis(4-nitrophenyl)phosphate) catalyzed by the mononuclear zinc(II):OH- complex of 1,5,9-triazacyclododecane (Zn:([12] aneN(3))). We present a binding mode in which one terminal phosphoryl oxygen atom as well as the nucleophilic group (hydroxyl anion) binds to zinc center. Two potential mechanisms were found as follows: one is a concerted mechanism with a reaction barrier of 18.1 kcal/mol in liquid phase of implicit solvent and 13.8 kcal/mol in liquid phase of explicit solvent of water molecules; the other is a stepwise mechanism with a hydroxylated phosphate reaction intermediate of a quasi-trigonal bipyramid configuration but is less feasible. Both the concerted reaction pathway and stepwise reaction pathway are S(N)2 manner of nucleophilic substitution reactions. Meanwhile polar protic solvents like water, methanol and ethanol are favored in the catalyst-assisted hydrolysis mechanism. We explore the rationality of deprotonation of mono-anionic phosphates in the transient products and find that it is difficult to dissociate a proton and the ultimate product is NPP- rather than NPP2-. These results are consistent with and systematically interpret the experimental observations, more importantly, provide useful suggestions in the catalyst design and solvent selection. (C) 2012 Elsevier B.V. All rights reserved.