Currently, most neutralizing antibodies or vaccines are developed to target the RBD to block or inhibit viral infection.80,84–93 Furthermore, the binding with ACE2 of RBD requires conformational adaptation, and an easier transition from “closed” to “open” conformation of spike protein benefits the viral infection.32,94–96 Therefore, mutations in the spike protein of SARS-CoV-2 variants could significantly influence the structure of the spike protein conformation and further the interaction with ACE2 or neutralizing antibodies32,95,97–100 (Figs. 2b and  3). This evidence concerns the gene ACE2 and viral infectious disease.