In this DFT study, activities of 11 different N2O4, N2O3, and NO2 core containing Zr(IV) complexes, 4,13-diaza-18-crown-6 (I'N2O4), 1,4,10-trioxa-7,13-diazacyclopentadecane (I'N2O3), and 2-(2-methoxy)ethanol (I'NO2), 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 I'N2O4, and I'NO2 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)(OHH)(H2O/OH)n for n = 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 I'DNO2-2H 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.