Effects of the Metal Ion on the Mechanism of Phosphodiester Hydrolysis Catalyzed by Metal-Cyclen Complexes

In this study, mechanisms of phosphodiester hydrolysis catalyzed by six di- and tetravalent metal-cyclen (M-C) complexes (Zn-C, Cu-C, Co-C, Ce-C, Zr-C and Ti-C) have been investigated using DFT calculations. The activities of these complexes were studied using three distinct mechanisms: (1) direct attack (DA), (2) catalyst-assisted (CA), and (3) water-assisted (WA). All divalent metal complexes (Zn-C, Cu-C and Co-C) coordinated to the BNPP substrate in a monodentate fashion and activated its scissile phosphoester bond. However, all tetravalent metal complexes (Ce-C, Zr-C, and Ti-C) interacted with BNPP in a bidentate manner and strengthened this bond. The DAmechanism was energetically the most feasible for all divalent M-C complexes, while the WAmechanism was favored by the tetravalent complexes, except Ce-C. The divalent complexes were found to be more reactive than their tetravalent counterparts. Zn-C catalyzed the hydrolysis with the lowest barrier among all M-C complexes, while Ti-C was the most reactive tetravalent complex. The activities of Ce-C and Zr-C, except Ti-C, were improved with an increase in the coordination number of the metal ion. The structural and mechanistic information provided in this study will be very helpful in the development of more efficient metal complexes for this critical reaction

Effects of Ligand Environment in Zr(IV) Assisted Peptide Hydrolysis

In this DFT study, activities of 11 different N₂O₄, N₂O₃, and NO₂ core containing Zr­(IV) complexes, 4,13-diaza-18-crown-6 (<b>I′</b>_<b>N2O4</b>), 1,4,10-trioxa-7,13-diazacyclopentadecane (<b>I′</b>_<b>N2O3</b>), and 2-(2-methoxy)­ethanol (<b>I′</b>_<b>NO2</b>), respectively, and their analogues in peptide hydrolysis have been investigated. Based on the experimental information, these molecules were created by altering protonation states (singly protonated, doubly protonated, or doubly deprotonated) and number of their ligands. The energetics of the <b>I′</b>_<b>N2O4</b>, and <b>I′</b>_<b>NO2</b> and their analogues predicted that both stepwise and concerted mechanisms occurred either with similar barriers, or the latter was more favorable than the former. They also showed that the doubly deprotonated form hydrolyzed the peptide bond with substantially lower barriers than the barriers for other protonation states. For NO₂ core possessing complexes, Zr-(NO₂)­(OH^H)­(H₂O/OH)_<i>n</i> for <i>n</i> = 1–3, the hydroxyl group containing molecules were found to be more reactive than their water ligand possessing counterparts. The barriers for these complexes reduced with an increase in the coordination number (6–8) of the Zr­(IV) ion. Among all 11 molecules, the NO₂ core possessing and two hydroxyl group containing <b>I′</b>_{<b>DNO2–2H</b>} complex was found to be the most reactive complex with a barrier of 28.9 kcal/mol. Furthermore, barriers of 27.5, 28.9, and 32.0 kcal/mol for hydrolysis of Gly-Glu (negative), Gly-Gly (neutral), and Gly-Lys (positive) substrates, respectively, by this complex were in agreement with experiments. The activities of these complexes were explained in terms of basicity of their ligand environment and nucleophilicity of the Zr­(IV) center using metal–ligand distances, charge on the metal ion, and the metal–nucleophile distance as parameters. These results provide a deeper understanding of the functioning of these complexes and will help design Zr­(IV)-based synthetic metallopeptidases