Cooperative and structural relationships of the trimeric Spike with infectivity and antibody escape of the strains Delta (B.1.617.2) and Omicron (BA.2, BA.5, and BQ.1)

Author(s)

de Souza, Anacleto Silva ; de Souza, Robson Francisco ; Guzzo, Cristiane Rodrigues

• Document type: Journal article
• Source: Journal of Computer-Aided Molecular Design; v. 37, n. 12, p. 22-pg., 2023-10-04.

Abstract

Herein, we conducted simulations of trimeric Spike from several SARS-CoV-2 variants of concern (Delta and Omicron sub-variants BA.2, BA.5, and BQ.1) and investigated the mechanisms by which specific mutations confer resistance to neutralizing antibodies. We observed that the mutations primarily affect the cooperation between protein domains within and between protomers. The substitutions K417N and L452R expand hydrogen bonding interactions, reducing their interaction with neutralizing antibodies. By interacting with nearby residues, the K444T and N460K mutations in the SpikeBQ.1 variant potentially reduces solvent exposure, thereby promoting resistance to antibodies. We also examined the impact of D614G, P681R, and P681H substitutions on Spike protein structure that may be related to infectivity. The D614G substitution influences communication between a glycine residue and neighboring domains, affecting the transition between up- and -down RBD states. The P681R mutation, found in the Delta variant, enhances correlations between protein subunits, while the P681H mutation in Omicron sub-variants weakens long-range interactions that may be associated with reduced fusogenicity. Using a multiple linear regression model, we established a connection between inter-protomer communication and loss of sensitivity to neutralizing antibodies. Our findings underscore the importance of structural communication between protein domains and provide insights into potential mechanisms of immune evasion by SARS-CoV-2. Overall, this study deepens our understanding of how specific mutations impact SARS-CoV-2 infectivity and shed light on how the virus evades the immune system. (AU)

• FAPESP's process: 21/10577-0 - Biology of Bacteria and Bacteriophages Research Center
• Grantee: Shaker Chuck Farah
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 19/00195-2 - Understanding the c-di-GMP signaling networks and the Type II secretion system present into the human pathogen Leptospira interrogans Copenhageni
• Grantee: Cristiane Rodrigues Guzzo Carvalho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 21/00070-5 - Annual resource application plan for supporting institutional research infrastructure (ICB-USP 2018-2019)
• Grantee: Carlos Pelleschi Taborda
• Support Opportunities: Research Grants - Technical Reserve for Institutional Research Infrastructure
• FAPESP's process: 16/09047-8 - Comparative genomics of bacterial toxins associated with type IV secretion systems
• Grantee: Robson Francisco de Souza
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/04680-0 - Design of different fragments of SARS-CoV-2 surface protein spike for the development of fast diagnostic test and vaccine
• Grantee: Cristiane Rodrigues Guzzo Carvalho
• Support Opportunities: Regular Research Grants