Mechanistic investigation of the cleavage of phosphodiester catalyzed by a symmetrical oxyimine-based macrocyclic dinuclear zinc complex: a DFT study

Abstract

Density functional theory (DFT) was utilized to investigate the hydrolysis reaction mechanisms of phosphodiester BNPP (BNPP = bis(4-nitrophenyl)phosphate) catalyzed by a symmetrical oxyimine-based macrocyclic dinuclear zinc(ii) complex. We examined the nature of the nucleophilic reagent and the active form of the catalyst. The coordination and binding models of the catalyst-substrate complex were explored and we investigated two catalyst configurations (a ridge configuration and a plane configuration), four basic catalyst-substrate binding models (a mono-point-binding model, a dual-point-binding model, an OH-bridging model and a mono-center-dual-binding model) and two alternate roles for the metal-coordinated hydroxide ion (whether it acts as a nucleophile or as a general base to facilitate the deprotonation of a solvent molecule). The one-point-binding mode was found to be preferred to construct a starting reactant. Nine plausible reaction mechanisms were proposed and investigated. Mechanism 1, a stepwise SN2-type addition-substitution reaction involving a para-position nucleophilic attack and the configuration inversion of the phosphate, was found to be the most favorable pathway. All of the proposed pathways are derived from alternate mechanisms such as a ping-pong mechanism and an AP mechanism. The ping-pong mechanism in combination with the role of the metal-coordinated hydroxide ion acting as a nucleophile was found to be more competitive than the other mechanisms examined. Results reported in this paper are consistent with, and can be utilized to systematically interpret, the experimental observations in the literature.

Phosphatase models: Synthesis, structure and catalytic activity of zinc complexes derived from a phenolic Mannich-base ligand

“…The coordination patterns and binding models of the catalystsubstrate complex have been largely explored in literature [15,16,20,30,42] and after rigorous considerations two plausible catalytic cycles having reasonably good agreement with our kinetic results have been postulated from the previous representative mechanisms. The substrate molecule binds as a dianionic mononitrophenyl phosphate to the complex having phosphatase activity.…”

Nuclease-like metalloscissors: Biomimetic candidates for cancer and bacterial and viral infections therapy

“…These methodologies are able to probe the mechanism of cleavage reaction through analysis of all the involved intermediates and transition states throughout the catalytic process. These methods are able to predict the effective factors on the nuclease activity of AMSs [164] , [165] , [166] , [167] , [168] , [169] , [170] , [171] , [172] , [173] , [174] . Moreover, the photophysical properties of metal complexes suitable for the use in PDT have been investigated by DFT and time-dependent DFT (TD-DFT) approaches [175] .…”

Mechanistic Studies of Homo- and Heterodinuclear Zinc Phosphoesterase Mimics: What Has Been Learned?

“…DFT studies on the dizinc(II) complex of an analogous N 5 O 2 ligand containing two 1-methylimidazole moieties (Das et al, 2018) and on the related unsymmetric dizinc(II) complex [Zn 2 L4 (μ-OH)(OH)] found the same mechanism (Daver et al, 2016). By contrast, DFT calculations of the hydrolysis of BNPP by trans -[Zn 2 ( L1 a )(H 2 O)(OH)] + suggested a stepwise mechanism involving nucleophilic attack by a terminally Zn-bound hydroxide and formation of the phosphorane intermediate as the rate-determining step (Zhang et al, 2014b). In the calculated mechanism bridging substrate binding also takes place in a stepwise manner with the phosphodiester binding initially via one phosphoryl oxygen to one Zn(II), followed by the formation of a second coordination bond between the nucleophile-binding Zn(II) and the other phosphoryl oxygen.…”