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Comparative Study of the Mutations Observed in the SARS-CoV-2 RBD Variants of Concern and Their Impact on the

Mariem Ghoula1, Audrey Deyawe Kongmeneck1, Rita Eid1

  • 1Université de Paris, CNRS, INSERM, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France.

The Journal of Physical Chemistry. B
|September 29, 2023
PubMed

Insights

New SARS-CoV-2 variants exhibit increased ACE2 binding affinity and potential antibody evasion. Key mutations in the spike protein

Area of Science:

  • Virology
  • Structural Biology
  • Computational Biology

Background:

  • The emergence of SARS-CoV-2 variants of concern (VOCs) significantly impacts COVID-19's global health burden.
  • The spike protein's receptor-binding domain (RBD) is crucial for viral entry and a key target for therapeutic interventions.
  • Genetic variations in SARS-CoV-2, particularly in the spike protein, can alter viral properties like transmissibility and virulence.

Purpose of the Study:

  • To investigate the structural and biophysical changes in SARS-CoV-2 VOCs affecting ACE2 binding and antibody evasion.
  • To identify specific amino acid residues responsible for altered viral affinity and immune escape mechanisms.
  • To compare the binding characteristics of different SARS-CoV-2 variants with the human ACE2 receptor.

Main Methods:

  • Reconstruction of various SARS-CoV-2 variants of concern.
  • Molecular dynamics (MD) simulations to analyze the stability of the ACE2-RBD complex.
  • Free energy calculations to assess binding affinities and biophysical properties.
  • Detailed structural analysis of key residues within the RBD.

Main Results:

  • SARS-CoV-2 VOCs demonstrate a higher binding affinity to ACE2 compared to the ancestral Wuhan strain.
  • Specific mutations, including K417N and E484K/A, are implicated in antibody evasion.
  • Mutations Q498R and N501Y enhance the RBD's affinity for ACE2, potentially increasing viral infectivity.
  • Identification of crucial residues maintaining a balance between ACE2 affinity and antibody evasion.

Conclusions:

  • SARS-CoV-2 variants possess enhanced binding to ACE2, contributing to their increased prevalence.
  • Understanding these structural and functional changes is vital for developing effective antiviral strategies and vaccines.
  • Targeting specific mutations may offer a pathway to counter the evolution of SARS-CoV-2 VOCs.

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