Molecular simulation studies of the interactions between the human/pangolin/cat/bat ACE2 and the receptor binding domain of the SARS-CoV-2 spike protein.

The recent outbreak of SARS-CoV-2 has had a profound effect on the world. Similar to that in SARS-CoV, the entry receptor of SARS-CoV-2 is ACE2. The binding of SARS-CoV-2 spike protein to ACE2 is the critical to the virus infection. Recently multiple species (human, Chinese chrysanthemum, Malay pangolin and cat) have been reported to be susceptible to the virus infection. However, the binding capacity and the detailed binding mechanism of SARS-CoV-2 spike protein to ACE2 of these species remains unexplored. Herein free energy calculations with MM-GBSA and Potential of Mean Forces together reveal that the Human-SARS-CoV-2 has a higher stability tendency than Human-SARS-CoV. Meanwhile, we uncover that SARS-CoV-2 has an enhanced ability to bind with the ACE2 in humans, pangolins and cats compared to that in bats. Analysis of key residues with energy decomposition and residue contact maps reveal several important consensus sites in ACE2s among the studied species, and determined the more favorable specified residues among the different types of amino acids. These results provide important implications for understanding SARS-CoV-2 host range which will make it possible to control the spread of the virus and use of animal models, targeted drug screening and vaccine candidates against SARS-CoV-2. • The SARS-CoV-2 showed stronger binding to intermediate host than to bat host. • Studied species has the same key active-site residues to association with RBD. • Several specific residue types in ACE2 are susceptible to SARS-CoV-2 infection. • MD results complement previous cryo-EM studies on the SARS-CoV-2 enzyme. [ABSTRACT FROM AUTHOR]