Molecular evolution and structural analyses of the spike glycoprotein from Brazilian SARS-CoV-2 genomes: the impact of selected mutations

Abstract

The COVID-19 pandemic caused by SARS-CoV-2 has reached by February 2022 more than 380 million cases and 5.5 million deaths worldwide since its beginning in late 2019, leading to enhanced concern in the scientific community and the general population. One of the most important pieces of this host-pathogen interaction is the spike protein, which binds to the hACE2 cell receptor, mediates the membrane fusion and is the major target of neutralizing antibodies against SARS-CoV-2. The multiple amino acid substitutions observed in this region, specially in RBD have enhanced the hACE2 binding affinity and led to several modifications in the mechanisms of SARS-CoV-2 pathogenesis, improving the viral fitness and/or promoting immune evasion, with potential impact in the vaccine development. In this work, we identified 48 sites under selective pressures, 17 of them with the strongest evidence by the HyPhy tests, including VOC related mutation sites 138, 142, 222, 262, 484, 681, and 845, among others. The coevolutionary analysis identified 28 sites found not to be conditionally independent, such as E484K-N501Y. The molecular dynamics and free energy estimates showed the structural stabilizing effect and the higher impact of E484K for enhanced binding affinity between the spike RBD and hACE2 in P.1 and P.2 lineages (specially with L452V). Structural changes were also identified in the hACE molecule when interacting with B.1.1.7 RDB. Despite some destabilizing substitutions, a stabilizing effect was identified for the majority of the positively selected mutations.

Communicated by Ramaswamy H. Sarma

Keywords:

• Covid-19
• severe acute respiratory syndrome coronavirus 2
• infectious diseases
• spike
• positive selection
• molecular evolution

Acknowledgements

We thank Amanda M. Mayer for suggestions in the introduction section. We also thank the administrators of the GISAID database and research groups across the world for supporting the rapid and transparent sharing of genomic data during the COVID-19 pandemic.

Disclosure statement

The authors declare no competing interests.

Funding

Scholarships and Fellowships were supplied by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001 and Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA). The funders had no role in the study design, data generation and analysis, decision to publish or the preparation of the manuscript. P. A. N. acknowledges financial support from CNPq and CAPES (Financial code 001), as well as the Centro Nacional de Supercomputação (CESUP), Universidade Federal do Rio Grande do Sul (UFRGS) for providing HPC resources.

Authors’ contributions

Conceptualization: Patrícia Aline Gröhs Ferrareze, Claudia Elizabeth Thompson; Methodology: Patrícia Aline Gröhs Ferrareze, Paulo Augusto Netz, Claudia Elizabeth Thompson; Formal analysis and investigation: Patrícia Aline Gröhs Ferrareze, Ricardo Ariel Zimerman, Vinicius Bonetti Francheschi, Paulo Augusto Netz, Claudia Elizabeth Thompson; Writing - original draft preparation: Patrícia Aline Gröhs Ferrareze, Ricardo Ariel Zimerman, Vinicius Bonetti Francheschi, Gabriel Dickin Caldana, Paulo Augusto Netz, Claudia Elizabeth Thompson; Writing - review and editing: Patrícia Aline Gröhs Ferrareze, Ricardo Ariel Zimerman, Vinicius Bonetti Francheschi, Gabriel Dickin Caldana, Paulo Augusto Netz, Claudia Elizabeth Thompson; Funding acquisition: Claudia Elizabeth Thompson; Resources: Claudia Elizabeth Thompson; Supervision: Claudia Elizabeth Thompson. All authors have read and approved the manuscript.

Availability of data and materials

Full tables acknowledging the authors and corresponding labs submitting sequencing data used in this study can be found in Supplementary File 1. Additional information used and/or analysed during the current study are available from the corresponding author on reasonable request.