RBD mutations from circulating SARS-CoV-2 strains enhance the structure stability and infectivity of the spike protein

A novel zoonotic coronavirus SARS-CoV-2 is associated with the current global pandemic of Coronavirus Disease 2019 (COVID-19). Bats and pangolins are suspected as the reservoir and the intermediate host. The receptor binding domain (RBD) of the SARS-CoV-2 S protein plays the key role in the tight binding to human ACE2 for viral entry. In this study, we analyzed the worldwide RBD mutations and found 10 mutants revealed high positive selection pressure during the spread. The equilibrium dissociation constant (KD) of three RBD mutants were two orders of magnitude lower than the prototype Wuhan-Hu-1 strain due to the stabilization of the beta-sheet scaffold of the RBD. This indicated that the mutated viruses have evolved to acquire remarkably increased infectivity. The KD values for the bat and the pangolin SARS-like CoV RBDs indicated that it would be difficult and unlikely for this bat SARS-like CoV to infect humans; however, the pangolin CoV is potentially infectious to humans with respect to its RBD. These analyses of critical mutations of the RBD provide further insights into the molecular evolution of SARS-CoV-2, presumably while under selection pressure. This enhancement of the SARS-CoV-2 binding affinity to its host receptor ACE2 reveals a higher risk of more severe infections during a sustained pandemic of COVID-19 if no effective precautions are implemented.