Biophysical characterization of the SARS-CoV2 spike protein binding with the ACE2 receptor explains increased COVID-19 pathogenesis

Ratul Chowdhury; Costas D Maranas

These results imply that the SARS-CoV-2 RBDs of the spike protein are highly optimized for binding with ACE2. We note that positions Lys417 and Gly502 have the strongest impact on binding (75% and 83% reduction upon mutation to Ala, respectively). This is because they help establish one strong electrostatic contact with Asp30, and three with Gln325, Lys353, and Gly354 (as listed in Table 1 ). Our results also identify the same three residues Phe486, Gln493, and Asn501 to be important for ACE2 binding as proposed by Wan et al. 2 . In their study, they used a homology modeled SARS-CoV-2 RBD description instead of experimentally resolved atomic coordinates to model the protein binding event. We predict that Phe486, Gln493, and Asn501 establish three new contacts each (see Table 1 for interaction partners and inter-residue distances), and their mutation to Ala (even for only one of them) leads to loss of ACE2 binding by more than ~62.5%. coronavirus. Bars represent the residual ACE2 binding score upon alanine mutation at the indicated site normalized with respect to binding score prior to mutation.