Adaptive string method QM/MM simulations of the complete peptide hydrolysis along the minimum free energy path revealed a significant difference in activation free energy of approximately 6.1 kcal mol -1 between oxytocin and angiotensin IV. Oxytocin cleavage was found to proceed via a concerted but asynchronous mechanism, forming a tetrahedral intermediate stabilized by electron donation from the scissile nitrogen lone pair to the σ-hole of the adjacent disulfide bond. In contrast, angiotensin IV did not form a stable intermediate, exhibiting distinct geometric features in its tetrahedral intermediate. These included bidentate zinc coordination and unfavourable conformational changes, resulting in steric repulsion between bulky valine side chain and hybridizing nitrogen atom's lone pair. These distinctive intermolecular interactions were elucidated through the application of high-level electronic structure calculations in the enzyme environment. The characterization was primarily conducted utilizing natural bond orbital (NBO) theory and non-covalent interaction (NCI) analysis.