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Enhanced Binding of SARS-CoV-2 Spike Protein to Receptor by Distal Polybasic Cleavage Sites.
ACS Nano. 2020 08 25; 14(8):10616-10623.AN

Abstract

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein plays a crucial role in binding the human cell receptor ACE2 that is required for viral entry. Many studies have been conducted to target the structures of RBD-ACE2 binding and to design RBD-targeting vaccines and drugs. Nevertheless, mutations distal from the SARS-CoV-2 RBD also impact its transmissibility and antibody can target non-RBD regions, suggesting the incomplete role of the RBD region in the spike protein-ACE2 binding. Here, in order to elucidate distant binding mechanisms, we analyze complexes of ACE2 with the wild-type spike protein and with key mutants via large-scale all-atom explicit solvent molecular dynamics simulations. We find that though distributed approximately 10 nm away from the RBD, the SARS-CoV-2 polybasic cleavage sites enhance, via electrostatic interactions and hydration, the RBD-ACE2 binding affinity. A negatively charged tetrapeptide (GluGluLeuGlu) is then designed to neutralize the positively charged arginine on the polybasic cleavage sites. We find that the tetrapeptide GluGluLeuGlu binds to one of the three polybasic cleavage sites of the SARS-CoV-2 spike protein lessening by 34% the RBD-ACE2 binding strength. This significant binding energy reduction demonstrates the feasibility to neutralize RBD-ACE2 binding by targeting this specific polybasic cleavage site. Our work enhances understanding of the binding mechanism of SARS-CoV-2 to ACE2, which may aid the design of therapeutics for COVID-19 infection.

Authors

No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

32806067

Citation

Qiao, Baofu, and Monica Olvera de la Cruz. "Enhanced Binding of SARS-CoV-2 Spike Protein to Receptor By Distal Polybasic Cleavage Sites." ACS Nano, vol. 14, no. 8, 2020, pp. 10616-10623.
Qiao B, Olvera de la Cruz M. Enhanced Binding of SARS-CoV-2 Spike Protein to Receptor by Distal Polybasic Cleavage Sites. ACS Nano. 2020;14(8):10616-10623.
Qiao, B., & Olvera de la Cruz, M. (2020). Enhanced Binding of SARS-CoV-2 Spike Protein to Receptor by Distal Polybasic Cleavage Sites. ACS Nano, 14(8), 10616-10623. https://doi.org/10.1021/acsnano.0c04798
Qiao B, Olvera de la Cruz M. Enhanced Binding of SARS-CoV-2 Spike Protein to Receptor By Distal Polybasic Cleavage Sites. ACS Nano. 2020 08 25;14(8):10616-10623. PubMed PMID: 32806067.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced Binding of SARS-CoV-2 Spike Protein to Receptor by Distal Polybasic Cleavage Sites. AU - Qiao,Baofu, AU - Olvera de la Cruz,Monica, Y1 - 2020/08/04/ PY - 2020/8/19/pubmed PY - 2020/9/15/medline PY - 2020/8/19/entrez KW - COVID-19 KW - SARS-CoV-2 KW - molecular dynamics simulations KW - peptide inhibitor KW - polybasic cleavage sites SP - 10616 EP - 10623 JF - ACS nano JO - ACS Nano VL - 14 IS - 8 N2 - The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein plays a crucial role in binding the human cell receptor ACE2 that is required for viral entry. Many studies have been conducted to target the structures of RBD-ACE2 binding and to design RBD-targeting vaccines and drugs. Nevertheless, mutations distal from the SARS-CoV-2 RBD also impact its transmissibility and antibody can target non-RBD regions, suggesting the incomplete role of the RBD region in the spike protein-ACE2 binding. Here, in order to elucidate distant binding mechanisms, we analyze complexes of ACE2 with the wild-type spike protein and with key mutants via large-scale all-atom explicit solvent molecular dynamics simulations. We find that though distributed approximately 10 nm away from the RBD, the SARS-CoV-2 polybasic cleavage sites enhance, via electrostatic interactions and hydration, the RBD-ACE2 binding affinity. A negatively charged tetrapeptide (GluGluLeuGlu) is then designed to neutralize the positively charged arginine on the polybasic cleavage sites. We find that the tetrapeptide GluGluLeuGlu binds to one of the three polybasic cleavage sites of the SARS-CoV-2 spike protein lessening by 34% the RBD-ACE2 binding strength. This significant binding energy reduction demonstrates the feasibility to neutralize RBD-ACE2 binding by targeting this specific polybasic cleavage site. Our work enhances understanding of the binding mechanism of SARS-CoV-2 to ACE2, which may aid the design of therapeutics for COVID-19 infection. SN - 1936-086X UR - https://www.unboundmedicine.com/medline/citation/32806067/Enhanced_Binding_of_SARS_CoV_2_Spike_Protein_to_Receptor_by_Distal_Polybasic_Cleavage_Sites_ L2 - https://doi.org/10.1021/acsnano.0c04798 DB - PRIME DP - Unbound Medicine ER -