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)

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: Journal of Computer-Aided Molecular Design; v. 37, n. 12, p. 22-pg., 2023-10-04.

Resumo

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)

• Processo FAPESP: 21/10577-0 - Centro de Pesquisa em Biologia de Bactérias e Bacteriófagos (CEPID B3)
• Beneficiário: Shaker Chuck Farah
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 19/00195-2 - Compreensão das redes de sinalização c-di-GMP e do sistema de secreção tipo II presentes no patógeno humano Leptospira interrogans Copenhageni
• Beneficiário: Cristiane Rodrigues Guzzo Carvalho
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/00070-5 - Plano anual de aplicação dos recursos para apoio à infra-estrutura institucional à pesquisa (ICB-USP anos base 2018 e 2019)
• Beneficiário: Carlos Pelleschi Taborda
• Modalidade de apoio: Auxílio à Pesquisa - Reserva Técnica para Infraestrutura Institucional de Pesquisa
• Processo FAPESP: 16/09047-8 - Genômica comparativa de toxinas bacterianas associadas ao sistema secretório do tipo IV
• Beneficiário: Robson Francisco de Souza
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 20/04680-0 - Desenho de diferentes fragmentos da proteína de superfície, spike, do SARS-CoV-2, para desenvolvimento de testes rápidos e de vacina
• Beneficiário: Cristiane Rodrigues Guzzo Carvalho
• Modalidade de apoio: Auxílio à Pesquisa - Regular