Stoichiometric Insights into SARS-CoV-2 Spike-ACE2 Binding Across Variants

The SARS-CoV-2 spike protein binds to the angiotensin-converting enzyme 2 (ACE2) receptor to mediate viral entry, with mutations in different variants influencing binding affinity and conformational dynamics. Using large-scale molecular dynamics simulations, we analyzed the Spike-ACE2 complex in the wild-type (WT), Beta, and Delta variants. Our findings reveal significant conformational rearrangements at the inter-face in Beta and Delta compared to WT, leading to distinct interaction networks and changes in complex stability. Binding free energy analysis further highlights variant-specific differences in ACE2 affinity, with alternative binding modes emerging over the simulation. The results enhance our understanding of spike-ACE2 stoichiometry across variants, providing implications for viral infectivity and therapeutic targeting.