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.

Characterization of peptides from common bean protein isolates and their potential to inhibit markers of type‐2 diabetes, hypertension and oxidative stress

“…The main interactions of the peptides were within the catalytic cavity with 8–12 amino acid residues, depending on the peptide, out of the total 38 amino acids comprising the catalytic cavity, and particularly with His353, known to play an important role in ACE activity. Zinc is essential for the activity of ACE, whose binding motifs are His383, Glu384, His387 and Glu411 . Molecular docking showed that the pure peptides interacted with His383 and Glu384, amino acids involved with zinc binding; thus this interaction potentially restrains ACE activity.…”

“…Zinc is essential for the activity of ACE, whose binding motifs are His383, Glu384, His387 and Glu411. 43 Molecular docking showed that the pure peptides interacted with His383 and Glu384, amino acids involved with zinc binding; thus this interaction potentially restrains ACE activity.…”

A comparative study of trypsin specificity based on QM/MM molecular dynamics simulation and QM/MM GBSA calculation

“…At present, QM/MM method and MD simulations have been combined to successfully study the inhibitorprotein interactions, functions of metalloproteins, and enzyme catalysis (Abdel-Azeim, Li, Chung, & Morokuma, 2011;Chen, Liang, Wang, Yi, Zhang, & Zhang, 2014;Duan, Mei, Zhang, Zhang, & Zhang, 2010;Duan, Mei, Zhang, & Zhang, 2009;Fan, Cembran, Ma, & Gao, 2013;Gao, Lu, Duan, Zhang, & Mei, 2011;Hou & Cui, 2013;Hou, McLaughlin, & Wang, 2007;Hu, Zhu, Zhang, Wang, & Zhang, 2010;Hu & Wang,2014;Ke, Wang, Xie, & Zhang, 2009;Keerthana & Kolandaivel, 2014;Meher, Kumar, & Bandyopadhyay, 2014;Smith, Ke, Guo, & Hengge, 2011;Wang et al, 2010Wang et al, , 2013Wang, Wu, Xu, Xie, & Guo, 2011;Wong, Richard, & Gao, 2009;Zhu, He, & Zhang, 2012;Zhu, Xiao et al, 2013). This method can take the polarizable electrostatic effect into account explicitly and accurately treat hydrogen bonding interactions.…”

QM/MM Study and MD Simulations on the Hypertension Regulator Angiotensin-Converting Enzyme

“…Due to its dual action, ACE inhibitors were one of the first line therapies in hypertensive and cardiovascular disorders for several years. [12][13][14][15][16][17][18][19][20][21][22][23] Very recently, Zhang C and coworkers 12 have suggested that the hydrolytic reaction of ACE proceeds via a general acid-base mechanism with the nucleophilic attack of a water molecule on the carbonyl carbon of the scissile bond. 3 In humans, there are two isoforms of ACE that are expressed from the same gene in a tissue-specific manner: the 140-kDa somatic form (sACE) that is found in a variety of tissues and the 77-kDa testicular form (tACE), which is exclusively expressed in germinal cells.…”

“…13,14 However, the ACE catalytic mechanism previously described only considers the tetra-coordinated configuration. 13,14 However, the ACE catalytic mechanism previously described only considers the tetra-coordinated configuration.…”