title: Insight into the interactive residues between two domains of human somatic Angiotensin-converting enzyme and Angiotensin II by MM-PBSA calculation and steered molecular dynamics simulation.
abstract: Angiotensin-converting enzyme (ACE), a membrane-bound zinc metallopeptidase, catalyzes the formation of Angiotensin-II (AngII) and the deactivation of bradykinin in the renin-angiotensin-aldosterone and kallikrein-kinin systems. As a hydrolysis product of ACE, AngII is regarded as an inhibitor and displays stronger competitive inhibition in the C-domain than the N-domain of ACE. However, the AngII binding differences between the two domains and the mechanisms behind AngII dissociation from the C-domain are rarely explored. In this work, molecular docking, Molecular Mechanics/Poisson-Boltzmann Surface Area calculation, and steered molecular dynamics (SMD) are applied to explore the structures and interactions in the binding or unbinding of AngII with the two domains of human somatic ACE. Calculated free energy values suggest that the C-domain-AngII complex is more stable than the N-domain-AngII complex, consistent with available experimental data. SMD simulation results imply that electrostatic interaction is dominant in the dissociation of AngII from the C-domain. Moreover, Gln106, Asp121, Glu123, and Tyr213 may be the key residues in the unbinding pathway of AngII. The simulation results in our work provide insights into the interactions between the two domains of ACE and its natural peptide inhibitor AngII at a molecular level. Moreover, the results provide theoretical clues for the design of new inhibitors.
authors.affiliation: a State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , People's Republic of China.
authors.forename: Shan-shan
authors.initials: SS
authors.lastname: Guan
authors.affiliation: b Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education , School of Life Sciences, Jilin University , Changchun 130023 , People's Republic of China.
authors.forename: Wei-wei
authors.initials: WW
authors.lastname: Han
authors.affiliation: a State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: a State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry , Jilin University , Changchun 130023 , People's Republic of China.
authors.forename: Song
authors.initials: S
authors.lastname: Wang
authors.affiliation: c School of Life Sciences , Jilin University , Changchun 130012 , People's Republic of China.
authors.forename: Ya-ming
authors.initials: YM
authors.lastname: Shan
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000804:Angiotensin II / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D000596:Amino Acids; D000804:Angiotensin II; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A
keywords: Angiotensin II; Angiotensin-converting enzyme; MM-PBSA calculation; molecular docking; steered molecular dynamics simulation