The Coronaviridae family of viruses includes hundreds of viruses common in many different animal species and humans. Seven coronaviruses (CoVs) are known to cause disease in humans. Four of them show low pathogenicity and are endemic in humans and the other three CoV are particularly dangerous and highly pathogenic viruses, which underwent genetic changes rendering them able to jump the species barriers from animal host to humans and also to spread efficiently among humans. SARS-CoV-2 is the seventh coronavirus known to infect humans. The S protein mediates attachment and viral and host cell membrane fusion. The receptor-binding domains (RBDs) are regions in S protein responsible for receptor recognition. Human angiotensin-converting enzyme 2 (ACE2) is recognized by HCoV-NL63, SARS-CoV and SARS-CoV-2 as their functional receptor.
Interaction energy analysis were performed to unveil how precisely SARS-CoV-2 interacts with ACE2 by identifying which amino acid residues are responsible for the interactions across S protein-ACE2 interfaces and how they contribute to the strength, stability and specificity of S protein interactions.
Interaction energies acting on molecular recognition of ACE2 by HCoV-NL63, SARS-CoV and SARS-CoV-2 conduced to a naturally evolved RBD with different combinations of amino acids, providing SARS-CoV-2 binding interface more interacting residue pairs, more hydrogen bonds, increased number of residues engaged in hydrogen bonding, allowing for better distribution of hydrogen bond per residue in interface than SARS-CoV or HCoV-NL63, includes salt bridge, and adds new van der Waals contacts into the network.
Residues across the SARS-CoV and SARS-CoV -2 homologous sequences have been chosen to be remarkably evolutionary conserved in the regions mediating binding of these viruses because of their dominant hydrogen bonding contribution to binding stability to ACE2. SARS-CoV-2 achieves higher binding affinity than SARS-CoV and HCoV-NL63 to human ACE2 molecular recognition primarily by combining its richer interaction network and higher binding stability.
This study presents a comprehensive and quantitative analysis of interaction energies of the human ACE2 molecular recognition by CoVs that may contribute to further understand the higher infectivity and transmissibility of SARS-CoV-2 compared to SARS-CoV and HCoV-NL63, furthermore, this could help explain why SARS-CoV-2 has an enhanced ability for pathogenicity.