Mutation-driven adaptation of ACE2-RBD binding revealed by integrative molecular dynamics analysis

Area of Science:

• Molecular biology
• Structural biology
• Virology

Background:

• SARS-CoV-2 variants exhibit altered transmissibility due to mutations in the receptor-binding domain (RBD).
• Understanding the molecular mechanisms of ACE2-RBD interaction is crucial for tracking viral evolution.
• Previous studies offered insights but lacked a systematic, multi-faceted comparison across major variants.

Purpose of the Study:

• To investigate how residue variations in SARS-CoV-2 RBD affect binding to human ACE2.
• To systematically compare structural dynamics and interfacial interactions across wild-type and five major variants (Alpha, Beta, Gamma, Delta, Omicron).
• To elucidate conserved and adaptive mechanisms of viral receptor engagement.

Main Methods:

• Integrative molecular modeling combining molecular dynamics simulations.
• Dynamic cross-correlation and principal component analyses.
• Interfacial contact mapping, hydrogen-bond characterization, and energetic decomposition.

Main Results:

• A conserved hydrogen-bond framework (ACE2 residues S19, Q24, Y83 with RBD positions A475, S477, N487) persists across all variants.
• Delta and Omicron variants show distinct interfacial rearrangements with redistributed hydrophobic and electrostatic interactions.
• Principal component analysis distinguishes early (Alpha-Gamma) from later (Delta-Omicron) variant lineages, indicating progressive adaptation.

Conclusions:

• Mutations collectively modulate ACE2 recognition through conserved and adaptive interaction patterns.
• The persistent hydrogen-bond network acts as an evolutionary anchor for receptor binding.
• Findings provide mechanistic insights into variant evolution and a framework for therapeutic design.