Shedding Light on the Inhibitory Mechanisms of SARS-CoV-1/CoV-2 Spike Proteins by ACE2-Designed Peptides

Author(s)

Freitas, Frederico Campos ^[1] ; Borges Ferreira, Paulo Henrique ^[1] ; Favaro, Denize Cristina ^[2] ; de Oliveira, Ronaldo Junio ^[1]

Affiliation

^[1] Univ Fed Triangulo Mineiro, Inst Ciencias Exatas, Dept Fis, Lab Biofis Teor, BR-38064200 Uberaba, MG - Brazil

^[2] Univ Estadual Campinas, Inst Quim, Dept Quim Organ, BR-13083970 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 61, n. 3, p. 1226-1243, MAR 22 2021.
• Web of Science Citations: 7

Abstract

Angiotensin-converting enzyme 2 (ACE2) is the host cellular receptor that locks onto the surface spike protein of the 2002 SARS coronavirus (SARS-CoV-1) and of the novel, highly transmissible and deadly 2019 SARS-CoV-2, responsible for the COVID-19 pandemic. One strategy to avoid the virus infection is to design peptides by extracting the human ACE2 peptidase domain a c helix, which would bind to the coronavirus surface protein, preventing the virus entry into the host cells. The natural alpha(1)-helix peptide has a stronger affinity to SARS-CoV-2 than to SARS-CoV-1. Another peptide was designed by joining alpha(1) with the second portion of ACE2 that is far in the peptidase sequence yet grafted in the spike protein interface with ACE2. Previous studies have shown that, among several alpha(1)-based peptides, the hybrid peptidic scaffold is the one with the highest/strongest affinity for SARS-CoV-1, which is comparable to the full-length ACE2 affinity. In this work, binding and folding dynamics of the natural and designed ACE2-based peptides were simulated by the well-known coarse-grained structure-based model, with the computed thermodynamic quantities correlating with the experimental binding affinity data. Furthermore, theoretical kinetic analysis of native contact formation revealed the distinction between these processes in the presence of the different binding partners SARS-CoV-1 and SARS-CoV-2 spike domains. Additionally, our results indicate the existence of a two-state folding mechanism for the designed peptide en route to bind to the spike proteins, in contrast to a downhill mechanism for the natural alpha(1)-helix peptides. The presented low-cost simulation protocol demonstrated its efficiency in evaluating binding affinities and identifying the mechanisms involved in the neutralization of spike-ACE2 interaction by designed peptides. Finally, the protocol can be used as a computer-based screening of more potent designed peptides by experimentalists searching for new therapeutics against COVID-19. (AU)

• FAPESP's process: 17/26131-5 - The chaperome: study of the relationship of the structure of its components and the maintenance of proteostasis
• Grantee: Carlos Henrique Inacio Ramos
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/22822-3 - Structural and dynamical origins of catalytic differences between OXA-143 and OXA-231
• Grantee: Denize Cristina Favaro
• Support Opportunities: Scholarships abroad - Research