title: Inhibitor and substrate binding by angiotensin-converting enzyme: quantum mechanical/molecular mechanical molecular dynamics studies.
abstract: 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.
authors.affiliation: Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University , Chengdu, Sichuan 610064, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wu
authors.forename: Dingguo
authors.initials: D
authors.lastname: Xu
authors.forename: Daiqian
authors.initials: D
authors.lastname: Xie
authors.forename: Hua
authors.initials: H
authors.lastname: Guo
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015773:Enalaprilat / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D017706:Lisinopril / Q000737:chemistry; D008297:Male; D056004:Molecular Dynamics Simulation; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry*; D011485:Protein Binding; D011789:Quantum Theory; D013379:Substrate Specificity; D013737:Testis / Q000737:chemistry; D015032:Zinc / Q000737:chemistry*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A; D015773:Enalaprilat; D015032:Zinc