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

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.血管紧张素Ⅰ转换酶（Angiotensin-I converting enzyme, ACE）是一种双结构域二肽基羧肽酶，通过激肽释放酶-激肽与肾素-血管紧张素-醛固酮复合体调控血压，因此是治疗心血管系统疾病的关键药物靶点。当前诸多研究聚焦于筛选新型ACE抑制肽以实现血压调控。为探究ACE与其抑制剂间的相互作用机制，本研究采用分子动力学模拟手段。结果显示：(a) 三种抑制剂-蛋白复合物的二级结构未发生显著改变；(b) 亮氨酸-异亮氨酸-缬氨酸-苏氨酸（Leu-Ile-Val-Thr, LIVT）-ACE复合物的均方根偏差（root-mean-square deviation, RMSD）、回转半径（radius of gyration, Rg）及溶剂可及表面积（solvent-accessible surface area, SASA）值均显著高于其余体系；(c) 与酪氨酸-亮氨酸-缬氨酸-脯氨酸-组氨酸（Tyr-Leu-Val-Pro-His, YLVPH）及酪氨酸-亮氨酸-缬氨酸-精氨酸（Tyr-Leu-Val-Arg, YLVR）体系相比，LIVT的主链在Asp300-Val350区域运动更为剧烈，该结论可通过质心距离得以验证；(d) Asp300-Val350区域的主链运动或有助于ACE与其抑制剂之间的相互作用。本研究的理论结果可为ACE特异性抑制剂的后续开发设计提供参考。