The ASM simulations elucidate a marked difference in reacivity between the two peptides with IRAP. Specifically, the activation free energies for hydrolysis were determined to be 21.5 kcal mol -1 and 27.6 kcal mol -1 for oxytocin and angiotensin IV, respectively (Figure ). Qualitatively consistent PMF profiles were observed in ASM simulations initiated from the catalytic Glu465 in OE2 conformation (see Figure , SI).