Research Article: Structural and molecular basis of angiotensin-converting enzyme by computational modeling: Insights into the mechanisms of different inhibitors

Date Published: April 18, 2019

Publisher: Public Library of Science

Author(s): Li Fang, Mingxian Geng, Chunlei Liu, Ji Wang, Weihong Min, Jingsheng Liu, Claudio M. Soares.


Angiotensin-I converting enzyme (ACE) is a two-domain dipeptidylcarboxypeptidase involved in regulating blood pressure via the kallikrein-kininand renin-angiotensin-aldosterone complex. Therefore, ACE is a key drug target for the treatment of cardiovascular system diseases. At present many works are focus on searching for new inhibitory peptides of ACE to control the blood pressure. In order to exploit the interactions between ACE and its inhibitors, molecular dynamics simulations were used. The results showed that (a) the secondary structures of the three inhibitor-protein complexes did not change significantly; (b) root-mean-square deviation (RMSD), radius of gyration (Rg), and solvent-accessible surface area (SASA) values of Leu-Ile-Val-Thr (LIVT)-ACE complexes were significantly higher than that of other systems; (c) the backbone movement of LIVT was vigorous in Asp300-Val350, compared with that in Tyr-Leu-Val-Pro-His (YLVPH) and Tyr-Leu-Val-Arg(YLVR), as shown by the center-of-mass distance; and (d) the backbone movement of Asp300-Val350 may contribute to the interaction between ACE and its inhibitors. Our theoretical results will be helpful to further the design of specific inhibitors of ACE.

Partial Text

Angiotensin-I converting enzyme (ACE), also called peptidyldipeptidase A (EC, belongs to the type-I membrane-anchored dipeptidylcarboxypeptidase family and is involved in controlling blood pressure by regulating electrolyte homeostasis via the reninangiotensin system [1]. ACE is a zinc metallopeptidase that is has little sequence homology with the other members in peptide family [1]. A comparison of ACE with other proteins using the DALI server [2] showed that ACE has obvious homology with neurolysin [3], which is in the M3 family of oligopeptidases, and is similar to a carboxypeptidase of the M32 family of carboxypeptidases from the hyperthermophilic archaeon Pyrococcus furiosus [4]. Similar to ACE, neurolysin and carboxypeptidase are all metallopeptidases contained in the HEXXH active-site motif, which mostly has α-helices with very few β-structures.

Theoretical study can simply explain the structural changes required for designing a new peptide that binds to ACE. In this study, we presented a systematic investigation of the structural basis and energetic profile of peptides that inhibit ACE by using a number of distinct but complementary molecular modeling methods, including MD simulations and computational alanine scanning, which was for the first time employed to explore the peptides to investigate the molecular mechanisms underlying ACE-peptide conformational changes and interactions. We conclude that the docking between ACE and the inhibitors conformed to the geometry of the tunnel, and these results can be used in future MD simulations. Furthermore, the results from the MD simulations of the three systems showed that the backbone movement of LIVT was more vigorous in Asp300-Val350 compared with that of YLVPH and YLVR, and the center-of-mass distance between Ala170 and Thr302 of LIVT changed significantly.




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