Visualization of interfacial electrostatic complementarity reveals evolutionary changes in SARS-CoV-2 RBD–hACE2 interactions

Protein-protein interaction (PPI) between the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and human angiotensin-converting enzyme 2 (hACE2) plays a critical role in viral infections. Therefore, comprehensively understanding the effects of amino acid mutations in the RBD, which are associated with viral evolution, on this PPI is important. Recently, we developed a PPI analysis method called "visualization of interfacial electrostatic complementarity (VIINEC)." VIINEC provides an intuitive understanding of the effect of amino acid mutations on PPIs by visualizing the electrostatic potential (ESP) at the interface. In this study, we used VIINEC to study the RBD-hACE2 complexes of 15 SARS-CoV-2 variants. The results demonstrated clear alterations in the ESPs of the RBDs during viral evolution. Interestingly, despite the absence of mutations in hACE2, its ESP changed significantly in response to RBD mutations, maintaining high electrostatic complementarity across the variants. In addition, these adaptive ESP changes in hACE2 were attributed to switch-like conformational changes in four charged residues.