Elucidating the Roles of Distinct Chemical Factors in the Hydrolytic Activities of Hetero- and Homonuclear Synthetic Analogues of Binuclear Metalloenzymes

Abstract

In this study, hydrolytic activities of hetero-and homobinuclear metallovariants of an asymmetric (I) or symmetric (II) ligand with the Fe III -Zn II , Zn II -Zn II , and Cu II -Cu II cores (i.e., I FZ , I ZZ , and I CC or II FZ , II ZZ , and II CC , respectively) are investigated using DFT calculations through four distinct mechanisms: dissociative (DA), substrate-assisted (SA), water-assisted (WA), and associative (AS). Additionally, the effects of different nucleophiles (μ-OH, terminal-OH, and -O 2 H 3 ), coordination numbers, para substituents (-CH 3 , -Cl, and -NO 2 ) of the linker, and an external electric field on the energetics of these reactions are computed. The geometries, spin ground states, and substrate binding modes of the three metal centers for both asymmetric (I) and symmetric (II) ligands differ from each other. There is no Lewis acid activation of the bis(2,4-dinitrophenyl) phosphate (BDNPP) substrate, and hydrolysis is predominantly controlled by the nucleophilicity of the metal-bound hydroxyl ion. The electronic nature of the metal ions determines the activities of their complexes, and the homobinuclear I ZZ is found to be the most active complex. However, complexes formed with ligand I are not more active than their ligand-II-containing counterparts for all metal ions. The DFT calculations suggest that the DA pathway is the energetically most feasible among the four pathways. The terminal hydroxyl group is the strongest nucleophile, and the electrondonating -CH 3 group is the most suitable para substituent in the linker. Whereas the introduction of an external electric field along the reaction axis lowers the barrier for I FZ , it leaves that unchanged for I ZZ and increases that for I CC . These combined results in this study highlight the influence of distinct critical chemical factors such as the electronic nature of the metal ions, the ligand environment, as well as the linker and nucleophile on phosphoester hydrolysis. Insights gained will guide the design of the next generation of versatile metal complexes for a wide range of reactions and applications.

Distinct chemical factors in hydrolytic reactions catalyzed by metalloenzymes and metal complexes

“…224 However, as noticed above for other metal complexes, no Lewis acid activation of the substrate is observed and the catalyst-substrate interaction actually strengthens the scissile P-O bond by 0.04 Å in comparison to the corresponding bond in its free form. 227 That is in contrast to the activation of the scissile P-O bond of BNPP in the mechanisms utilized by GpdQ 210 and SgAP. 145 In an S N 2-type reaction, an in-line concerted attack of the Fe(III) bound hydroxyl nucleophile of FZ-I B on the electrophilic P atom of BDNPP leads to the cleavage of the scissile P-O bond with a barrier of 15.8 kcal mol À1 .…”

“…8b). 227 Here, Fe III is located in the N 2 O 2 site and Zn( ii ) in the N 3 O site. BDNPP is coordinated to the Zn( ii ) ion in a monodentate fashion which is supported by experimental data.…”

Molecular binding of different classes of organophosphates to methyl parathion hydrolase from Ochrobactrum species

“…By substituting the metal ion in vitro, it is observed that the enzyme demonstrates different mechanisms and activity. [37][38][39] This phenomenon is seen in various enzymes, such as glycerophosphodiesterase (GpdQ), 40,41 phosphotriesterase (PTE) from Pseudomonas diminuta, 42 and OP-degrading hydrolase from Agrobacterium radiobacter (OpdA). 43 Depending on the metal ion and ligand composition, these complexes adopt diverse geometries and electronic spin states.…”