Studies On The QSAR And The Molecular Mechanism Of ACE Inhibitory Tripeptides With Proline As C-terminal

Angiotensin converting enzyme(ACE) play a very important role in regulation of blood pressure. It is an important target for many antihypertensive drugs. Biological short peptides become popular because of their safety and easy absorption. In this paper, QSAR model of ACE inhibitory tripeptides with proline as C-terminal was built. According to the QASR model, potential ACE inhibitory tripeptides were synthetized and their inhibitory activities were test in vitro. In addition, the mechanism of reaction between the selected ACE inhibitory tripeptide was studied by molecular dynamic(MD) simulations and nuclear magnetic resonance(NMR).In first part, three models were built using partial least squares regression(PLS) based on Z-scales, ISA-ECI and MS-WHIM amino acid descriptors respectivly. The data consisted of 38 peptides with proline as C-terminal. The model based on Z-scales coded show the best reliability and prediction ability among the three models. Its 2, 2, R2 were 0.782, 0.824, and 0.857 respectively. The model predicted activities of ten tripeptides, and four of them(IIP, IVP, VIP, IGP) were synthetized for activities test.In second part, the detection wavelength was modified from 474 nm to 492 nm, and the ratio of quinoline and benzene sulfochloride was improved from 3:1 to 8:1. The activities of four synthetized tripeptides were test by the improved activity test. The activity value of IIP by the experiment validation was very closed to its predicted value, the fractional error was only 2.51%. Fractional error between experiment and predicted activity value of IVP, IGP, VIP were 14.69%, 23.20%, 48.57% respectively. The result proved that the predicted ability of the QSAR model were good.In third part, the conformations of IIP in water and DMSO solution were studied by molecular dynamic(MD) simulation and NMR experiment. In aqueous solution, Extend conformation was the major conformation of IIP molecule. IIP molecule was very flexible in water; and it can shift between extended and folded states. The flexibility of IIP molecule was not observed in DMSO solution. This was proven by the 2D-NOESY experiment.In fourth part, the mechanism of interaction between IIP and ACE was studied by molecular docking and molecular dynamic simulation. The energy between pyrrole ring in IIP molecule and the hydrophobic region in ACE molecule and the hydrogen bond between the first place isoleucine in IIP and Lys-475 in ACE molecule were the major binding energy. In IIP molecule, the third place proline has the most influence on activity value, followed by the first place isoleucine and the second place isoleucine. This accorded with the result of QSAR model.In this paper, a systematic method was established by the combination of theory and experiment research. The method include QSAR model establishment, activity prediction, synthesis of potential ACE inhibitory peptides, activity test in vitro, and the explaination of relationship between activity and structure at a micro level.