Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein

Abstract

The recent pandemic of COVID-19, caused by SARS-CoV-2, is unarguably the most fearsome compared with the earlier outbreaks caused by other coronaviruses, SARS-CoV and MERS-CoV. Human ACE2 is now established as a receptor for the SARS-CoV-2 spike protein. Where variations in the viral spike protein, in turn, lead to the cross-species transmission of the virus, genetic variations in the host receptor ACE2 may also contribute to the susceptibility and/or resistance against the viral infection. This study aims to explore the binding of the proteins encoded by different human ACE2 allelic variants with SARS-CoV-2 spike protein. Briefly, coding variants of ACE2 corresponding to the reported binding sites for its attachment with coronavirus spike protein were selected and molecular models of these variants were constructed by homology modeling. The models were then superimposed over the native ACE2 and ACE2-spike protein complex, to observe structural changes in the ACE2 variants and their intermolecular interactions with SARS-CoV-2 spike protein, respectively. Despite strong overall structural similarities, the spatial orientation of the key interacting residues varies in the ACE2 variants compared with the wild-type molecule. Most ACE2 variants showed a similar binding affinity for SARS-CoV-2 spike protein as observed in the complex structure of wild-type ACE2 and SARS-CoV-2 spike protein. However, ACE2 alleles, rs73635825 (S19P) and rs143936283 (E329G) showed noticeable variations in their intermolecular interactions with the viral spike protein. In summary, our data provide a structural basis of potential resistance against SARS-CoV-2 infection driven by ACE2 allelic variants.

Keywords: ACE2; COVID-19; SARS-CoV-2; spike protein.

Figure 1

Structure of angiotensin‐converting enzyme 2 (ACE2) allelic variants. Structural comparison of wild type (green) and 17 different allelic variants of ACE2 protein (differently colored) in (A) ribbon conformation and (B) Cα backbone. C, Ball and stick representation of key amino acids critical for interaction with coronavirus spike protein in wild‐type ACE2 (green) compared with the corresponding substituting amino acid (purple) in 17 different ACE2 allelic variants. D, Enlarged view of the boxed region (C), amino acid changes with corresponding single‐nucleotide polymorphism ids are labeled at respective positions

Figure 2

Interaction between angiotensin‐converting enzyme 2 (ACE2) allelic variants and SARS‐CoV‐2 spike protein. A, Ribbon representation of docking conformation of spike protein (gold) with wild‐type ACE2 (green) and its allelic variants (gray). B, Bar graph showing the number of different types of intermolecular contacts between ACE2 variants and SARS‐CoV‐2 spike protein. C, Intermolecular interactions between wild‐type ACE2 (gray ribbon) and SARS‐CoV‐2 spike protein (gold ribbon). Amino acids of ACE2 and spike protein are represented by purple and orange sticks; red, blue, and green dotted lines, respectively correspond to hydrogen bonds, electrostatic interactions, and hydrophobic interactions (see Supporting Information Figures for all ACE2 variants). D, Comparison of critical intermolecular interactions and binding affinity between different ACE2 variants complexed with SARS‐CoV‐2 spike protein, where green ticks and red crosses represent presence and absence of the interactions, respectively