Molecular Dynamics Simulation Study On The Binding Mechanism Of Angiotensin-converting Enzyme With Inhibitory Peptides

Hypertension is a critical risk factor in the development of cardiovascular diseasethat seriously affects health. Renin-angiotensin-aldosterone and kallikrein-kininsystems are the vital mechanisms regulating blood pressure, in which Angiotensin-converting enzyme (ACE) is a key factor in the regulation of their balance. ACEmainly catalyzes the release of the octapeptide Angiotensin II (AngⅡ) from thedecapeptide Angiotensin I (AngI). ACE also cleaves the C-terminal dipeptide frombradykinin, which causes the formation of an inactive heptapeptide. The synergy ofthe ACE causes the rise of blood pressure in human body. Somatic ACE (sACE) is anisoforms of ACE, which comprises two protein domains N-domain and C-domain(which share~60%amino acid sequence identity) with high homology; each domainhas a catalytic center involving a zinc ion. It has been shown that the C-domain ofsACE is sufficient to maintain the regulation of blood pressure in vivo and henceviewed as the dominant site of AngⅡ generation.Due to the special regulative function of ACE, it has long been regarded as anexcellent target for the treatment of hypertension and related cardiovascular diseases.Some synthetic drugs, such as enalapril, lisinopril, and captopril, are used to inhibit the activity of sACE to treat hypertension. However, these synthetic drugs have sideeffects. In recent years, some potent natural peptide inhibitors have been successfullyobtain from food such as, mushrooms, eggs, milk, beans and so on. These peptideshave attracted widespread attention due to their low side effects. In addition, in thelatest study, AngⅡ has been identified as an inhibitor that displays strongercompetitive inhibition toward the C-domain than the N-domain. The structural data ofhuman sACE C-domain with its hydrolysis product, AngⅡ, have been obtained fromthe crystalline structure. This founds provide a better research space for the futherstudy on mechanism of how natural peptides binding to ACE.In this study, molecular docking, molecular dynamics simulation, steeredmolecular dynamics simulation, and (Molecular Mechanics/Poisson-BoltzmannSurface Area, MM-PBSA) calculation are applied to study AngⅡ-peptide complexes.The main research content is divided into three aspects:(1) Through investigating the interactions between the two domains of ACE andits natural peptide inhibitor AngⅡ, and calculating the energy differences between twodomains, we try to seek theoretical support for the different inhibited potency ofAngⅡ.(2) AngⅡ, as a hydrolysis product of ACE, must leave the active site. We focusedon discuss the mechanisms and factors involved in unbinding from the active site.Understanding the mechanisms of binding and metabolism of inhibitors, particularly,natural peptide inhibitors, is necessary in searching for better inhibitors to avoid thedisadvantages of drug design. (3) It is reported that peptides RIGLF and AHEPVK which obtained from themushroom, Agaricus bisporus, have competitive inhibited potency against ACE. Weregard the peptides and C-domain as research objects to investigate the differentbinding modes of two complex systems. Moreover, we compare the differentinhibitory potency of two complexes by calculating the free energy.The molecular dynamics simulation results in our work could provide themechanism of how natural peptide inhibitors bind to ACE at molecular level and thepredicted binding modes will be helpful for the development of the design of newinhibitors.