Inhibitor and Substrate Binding by Angiotensin-Converting Enzyme: Quantum Mechanical/Molecular Mechanical Molecular Dynamics Studies

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• 作者：Xuemei Wang ; Shanshan Wu ; Dingguo Xu ; Daiqian Xie ; Hua Guo
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2011
• 出版时间：May 23, 2011
• 年：2011
• 卷：51
• 期：5
• 页码：1074-1082
• 全文大小：924K
• 年卷期：v.51,no.5(May 23, 2011)
• ISSN：1549-960X

文摘

Angiotensin-converting enzyme (ACE) is an important zinc-dependent hydrolase responsible for converting the inactive angiotensin I to the vasoconstrictor angiotensin II and for inactivating the vasodilator bradykinin. However, the substrate binding mode of ACE has not been completely understood. In this work, we propose a model for an ACE Michaelis complex based on two known X-ray structures of inhibitor-enzyme complexes. Specifically, the human testis angiotensin-converting enzyme (tACE) complexed with two clinic drugs were first investigated using a combined quantum mechanical and molecular mechanical (QM/MM) approach. The structural parameters obtained from the 550 ps molecular dynamics simulations are in excellent agreement with the X-ray structures, validating the QM/MM approach. Based on these structures, a model for the Michaelis complex was proposed and simulated using the same computational protocol. Implications to ACE catalysis are discussed.