Computational Design of Peptides to Block Binding of the SARS-CoV-2 Spike Protein to Human ACE2

Xiaoqiang Huang; Robin Pearce; Yang Zhang

Two peptide fragments (a.a. 22-44 and 351-357) from hACE2 (6m0j, chain A) were extracted because they were in extensive contact with SARS-CoV-2 RBD (6m0j, chain E). The positions 44 . CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.28.013607 doi: bioRxiv preprint and 351 were chosen because the distance between their Cα atoms was only 5.5 Å, and therefore only one residue was required to link them. To reduce the interference to the surrounding amino acids, the linker residue was initially chosen as glycine. The small loop, 44S-glycine-351L, was then reconstructed using MODELLER 24 , while the other parts of the whole peptide were kept constant; five similar loop conformations were produced and the one with the best DOPE score was selected. For the sake of simplifying the discussion, the initial hybrid peptide constructed in this manner was denoted as the wild-type (note that it was not a truly native peptide), and the complex structure of SARS-CoV-2 RBD/hACE2 hybrid peptide was used as the template for computational peptide design ( Figure 1B ).