Atomistic insight into the essential binding event of ACE2-derived peptides to the SARS-CoV-2 spike protein
Author:
Sarto Carolina1, Florez-Rueda Sebastián2, Arrar Mehrnoosh3, Hackenberger Christian P.R.2ORCID, Lauster Daniel4, Di Lella Santiago1
Affiliation:
1. Instituto de Química Biológica – Ciencias Exactas y Naturales – Conicet/Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria , Pabellón II , 4° Piso , C1428EGA Ciudad de Buenos Aires , Argentina 2. Leibniz Forschungsinstitut für Molekulare Pharmakologie (FMP) , Robert-Roessle-Strasse 10 , D-13125 Berlin , Germany 3. Instituto de Cálculo – Conicet/Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria , Intendente Güiraldes 2160 , Pabellón II , 2° Piso , C1428EGA Ciudad de Buenos Aires , Argentina 4. Institut für Biochemie und Chemie, Freie Universität Berlin , Arnimallee 22 , D-14195 Berlin , Germany
Abstract
Abstract
The pathogenic agent of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters into human cells through the interaction between the receptor binding domain (RBD) of its spike glycoprotein and the angiotensin-converting enzyme 2 (ACE2) receptor. Efforts have been made towards finding antivirals that block this interaction, therefore preventing infection. Here, we determined the binding affinity of ACE2-derived peptides to the RBD of SARS-CoV-2 experimentally and performed MD simulations in order to understand key characteristics of their interaction. One of the peptides, p6, binds to the RBD of SARS-CoV-2 with nM affinity. Although the ACE2-derived peptides retain conformational flexibility when bound to SARS-CoV-2 RBD, we identified residues T27 and K353 as critical anchors mediating the interaction. New ACE2-derived peptides were developed based on the p6-RBD interface analysis and expecting the native conformation of the ACE2 to be maintained. Furthermore, we found a correlation between the helicity in trifluoroethanol and the binding affinity to RBD of the new peptides. Under the hypothesis that the conservation of peptide secondary structure is decisive to the binding affinity, we developed a cyclized version of p6 which had more helicity than p6 and approximately half of its K
D value.
Funder
Bundesministerium für Bildung und Forschung Berlin University Alliance
Publisher
Walter de Gruyter GmbH
Subject
Clinical Biochemistry,Molecular Biology,Biochemistry
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