Molecular mechanism of the interactions between inhibitory tripeptides and angiotensin-converting enzyme

Angiotensin I-converting enzyme (ACE) is a key therapeutic target for combating hypertension and related cardiovascular diseases. ACE inhibitory peptides offer the prospect of enhanced potency, high specificity, and no or low side effect. The ACE inhibitory tripeptides LKP and IKP differ from each other by one amino acid but their inhibitory potencies for ACE differ significantly. To uncover the molecular mechanism underlying this phenomenon, we have investigated the tripeptide/ACE complexes through molecular dynamics simulations coupled with quantum mechanical simulations. Comparative structural analysis has identified a hydrophobic subsite in the active site of cACE comprising hydrophobic residues Val379, Val380, Phe457, Phe527, and Ala418. The interactions of the side chains of Leu and Ile with the hydrophobic residues determine the binding positions of N-terminal residues of the tripeptides, that influence the interaction of the residues of tripeptides with the active site of cACE. This work presents the molecular mechanism of the interactions between the inhibitory tripeptides and ACE, and deciphers the structural basis for the high affinity LKP inhibition of ACE.