Modeling Substrate Coordination to Zn-Bound Angiotensin Converting Enzyme 2

ABSTRACT

The Angiotensin Converting Enzyme 2 (ACE2) is a crucial regulator for the renin-angiotensin system. ACE2 converts the Angiotensin (Ang) II peptide into Ang 1-7 and thus promotes various anti-proliferative, anti-inflammatory and cardioprotective effects. In this study, we computationally designed several Ang II mutants to find a strong binding sequence to ACE2 receptor and examined the role of ligand substitution in the docking of native as well as mutant Ang II to the receptor. The peptide in the ACE2-peptide complex was coordinated to zinc (Zn) in the ACE2 cleft. The MD-generated root-mean-square deviation values were mostly similar between the native and mutant peptides considered in this work. The initial peptide-ACE2 poses were generated by molecular docking. The MD simulations used were post-processed by MM-PBSA to generate the binding free energies. All of the peptides studied here demonstrated negative binding free energies, which suggest that all the tested peptides form stable complexes with ACE2. Additionally, by examining the trends in the binding free energies calculated with different internal dielectric constants, it is evident that native Ang II and two of its variants have strongest binding to ACE2 receptor. Even though free energy measurements through classical MD simulation have certain limitations, in the absence of the availability of crystal structures of ACE2-peptide complexes, our work provides some structural insights for various Ang II analogs and how they may interact with a zinc atom within the active site of the enzyme. Copyright © 2022, The Author(s), under exclusive licence to Springer Nature B.V.