ACE2 fragment as a decoy for novel SARS-Cov-2 virus

Fabiana Renzi; Dario Ghersi

The amino acids in the human ACE2 receptor involved in viral protein binding span two back-to-back helices, α-helices 1 and 2, from Ser19 to Tyr83. Based on the per-residue energy breakdown obtained with RosettaDock, this area contributes almost 90 percent to the total interaction energy. An additional, point-wise binding feature is represented by Lys353 located in the connecting loop of a downstream beta-hairpin. Lys353 is anchored to the N-terminal ACE2 helix by Tyr41 and Asp38, and it contributes almost 10 percent of the total interaction energy. An additional small downstream helix contributes negligibly to the total binding energy. In addition, we compared these structural binding determinants with the results of mutagenesis experiments performed by Wong et al. on a SARS-Cov fragment of 193 aminoacids, corresponding to residues 318-510 of the full S-protein (14) . Of the two loops encompassing aa 452-454 and aa 434-437 in SARS-Cov-2 (corresponding to aa 460-469 and 447-450 in SARS-Cov and shown to be important in the binding to ACE2), only the first comes into contact with Lys31. The second loop is quite far away from the binding surface (not shown), and its involvement in binding might be indirect, probably affecting the folding of the viral protein fragment.