Impact of mutations on spike protein-ACE2 interactions through molecular dynamics simulations

Abstract

Elucidating how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants modulate binding between the receptor-binding domain (RBD) and the human Angiotensin-converting enzyme 2 (ACE2) receptor remains central to understanding viral evolution and guiding therapeutic design. This study presents a molecular dynamics (MD) investigation of ACE2–RBD complexes for the wild-type virus and five major variants, Alpha, Beta, Gamma, Delta, and Omicron, using an integrated computational framework that combines structural dynamics, interfacial contact mapping, hydrogen bonding profiles, and advanced network-based analysis. Hierarchical clustering of residue-level contact frequencies and interaction networks enabled classification of variant-specific binding strategies and evolutionary divergence. A conserved hydrogen bonding “anchor” network, centered on ACE2 residues S19, Q24, and Y83 and RBD residues A475, S477, and N487, was identified across all variants, suggesting structural constraints essential for receptor engagement. Conversely, Delta and Omicron displayed substantial interfacial rewiring, characterized by the loss of canonical interactions and the emergence of novel cation–π, π–π, and hydrophobic contacts. Principal component analysis revealed that the ACE2–RBD interface is comparatively less flexible than other regions, while clustering results delineated early versus late variant groups. This work demonstrates the utility of MD-driven contact network analysis and clustering approaches in uncovering conserved interfacial motifs and adaptive strategies, providing a computational framework for monitoring and interpreting the molecular evolution of emerging SARS-CoV-2 variants.