QM/MM molecular dynamics simulations of E-R complexes. QM/MM MD simulations were conducted to elucidate the mechanistic differences in IRAP's cleavage of the natural substrate oxytocin versus the competitive inhibitor angiotensin IV. Understanding these distinctions, despite similar binding modes, is crucial for rational inhibitor design targeting neurological and other disorders. First, unrestrained simulations were employed to probe peptideactive site interactions, focusing on catalytic residue flexibility and hydrogen bonding with the conserved GAMEN loop.