Subtle Changes at the RBD/hACE2 Interface During SARS-CoV-2 Variant Evolution: A Molecular Dynamics Study

Area of Science:

• Molecular biology
• Virology
• Biophysics

Background:

• SARS-CoV-2 Omicron variants display distinct characteristics from prior strains, notably lower morbidity despite increased transmissibility compared to the Delta variant.
• Understanding the molecular mechanisms underlying Omicron's infectivity and binding dynamics is crucial for public health.

Purpose of the Study:

• To investigate the dynamic interactions between the spike receptor-binding domain (RBD) of SARS-CoV-2 variants and the human angiotensin-converting enzyme 2 (hACE2) receptor.
• To elucidate the molecular basis for the differential binding stability and infectivity of Omicron variants relative to the Delta variant.

Main Methods:

• Molecular dynamics (MD) simulations were employed to model the spike RBD/hACE2 complexes for wild-type, Delta, and four Omicron variants.
• Analysis included residue interaction profiling using PairInt, hydrophobic potential calculations, and contact-based principal component analysis (PCA).

Main Results:

• PairInt analysis identified key residues involved in stable electrostatic interactions contributing to spike RBD-hACE2 binding.
• Omicron variants demonstrated significant contributions from apolar contacts, forming distinct hydrophobic patches.
• Subtle mutations, such as S375F common in Omicron, were linked to enhanced binding stability through contact network analysis.

Conclusions:

• The dynamic binding profile of Omicron variants to hACE2 differs significantly from the Delta variant, characterized by enhanced stability.
• Specific mutations within the Omicron spike RBD contribute to improved binding affinity and stability, potentially explaining its epidemiological success over Delta.