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Uncovering the Binding Mechanism of Mutated Omicron Variants via Computational Strategies

Sajjad Haider1, Nadeem Ahmad1, Muhammad Shafiq1

  • 1H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.

ACS Omega
|February 3, 2025
PubMed

Insights

New Omicron subvariants like XBB.1.5 and CH.1.1 show increased transmissibility due to enhanced binding stability with human ACE2 receptors. Molecular dynamics simulations reveal these variants bind more effectively than the wild-type Omicron.

Area of Science:

  • Virology and Molecular Biology
  • Computational Biology and Bioinformatics

Background:

  • The COVID-19 pandemic, caused by SARS-CoV-2, has seen the emergence of numerous Variants of Concern (VOCs), including Omicron.
  • Omicron variants, particularly subvariants like XBB.1.5 and CH.1.1, exhibit increased transmissibility, partly due to mutations in the spike protein's receptor-binding domain (RBD).
  • The spike protein's interaction with the human angiotensin-converting enzyme 2 (hACE2) receptor is crucial for viral entry and infectivity.

Purpose of the Study:

  • To investigate the molecular dynamics and binding stability of SARS-CoV-2 Omicron subvariants XBB.1.5 and CH.1.1 in complex with the human ACE2 receptor.
  • To compare the binding affinity and structural stability of these subvariants against the wild-type Omicron variant using computational methods.

Main Methods:

  • Employed in silico molecular dynamics (MD) simulations totaling 1.65 μs to analyze the structural stability of spike protein-hACE2 complexes.
  • Assessed structural stability using parameters such as root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg).
  • Determined binding free energies using the MM-GBSA (Molecular Mechanics with Generalized Born Surface Area) approach to quantify binding affinities.

Main Results:

  • Unbound mutant spike protein frameworks (SM and TM) showed greater instability compared to the wild-type (WT) Omicron.
  • The WT Omicron-hACE2 complex was less stable than the SM-hACE2 and TM-hACE2 complexes, indicating increased stability for the subvariants.
  • MM-GBSA calculations revealed higher binding free energy values for SM-hACE2 and TM-hACE2 complexes, suggesting more stable and ordered binding interactions.

Conclusions:

  • The enhanced binding stability and ordered interactions of Omicron subvariants XBB.1.5 and CH.1.1 with the hACE2 receptor contribute to their increased transmissibility.
  • Computational simulations provide valuable insights into the molecular mechanisms underlying the evolutionary advantage of new SARS-CoV-2 variants.

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