ACE2 peptide fragment interacts with several sites on the SARS-CoV-2 spike protein S1

Abstract

The influence of the peptide QAKTFLDKFNHEAEDLFYQ on the kinetics of the SARS-CoV-2 spike protein S1 binding to angiotensin-converting enzyme 2 (ACE2) was studied to model the interaction of the virus with its host cell. This peptide corresponds to the sequence 24–42 of the ACE2 α1 domain, which is the binding site for the S1 protein. The on-rate and off-rate of S1-ACE2 complex formation were measured in the presence of various peptide concentrations using Bio-Layer Interferometry (BLI). The formation of the S1-ACE2 complex was inhibited when the S1 protein was preincubated with the peptide, however, no significant inhibitory effect was observed in the absence of preincubation. Dissociation kinetics revealed that the peptide remained bound to the S1-ACE2 complex and stabilized this complex. This suggestion was confirmed by computational mapping of the S1 protein surface for peptide binding that revealed two additional sites, located at some distance from the receptor binding domain of S1. These additional binding sites may affect the interaction between the peptide, the S1 protein, and ACE2.

Design of protein-binding peptides with controlled binding affinity: the case of SARS-CoV-2 receptor binding domain and angiotensin-converting enzyme 2 derived peptides

“…To date, several experimental structures of the complex between ACE2 and the receptor-binding domain of the SARS-CoV-2 Spike protein have been determined, providing the structural basis for the specific interaction mechanism and highlighting the critical residues involved in the complex formation (Shang et al, 2020). Interestingly, the peptide "IEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTN" (residues 21-53) appears to mimic the major interacting portion of the ACE2 receptor to the SARS-CoV-2 Spike RBD (Kuznetsov et al, 2022). Therefore, it is not surprising that peptides of different lengths, including residues 24 to 53 of the ACE2 receptor, have commonly been reported to exhibit high affinity binding to various regions of the SARS-CoV-2 Spike protein (de Campos et al, 2021;Larue et al, 2021).…”