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

Ratul Chowdhury; Costas D Maranas

In silico alanine scanning to identify spike residues most important for ACE2 binding Each one of the ACE2 binding residues from the three viral spike RBDs was computationally mutated to alanine (one at a time) and the resultant ACE2-RBD complexes were energy minimized and scored using Rosetta force field. This procedure assesses how important is the identity of the native residues by defaulting them to alanine and observing whether this significantly affects binding. The percent loss of The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.30.015891 doi: bioRxiv preprint ACE2 binding upon an alanine mutation was used as a proxy score for assessing the importance of each RBD residue in binding and subsequent pathogenesis. The results from the alanine scan study (see Figure 2 ) reveal that 88% (15 out of 17) of the ACE2 interface residues of SARS-CoV-2 are important for complex formation. Even a single alanine mutation in any of these reduces the binding score by ~60%.