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

Xiaoqiang Huang; Robin Pearce; Yang Zhang

To further examine what interactions improved the binding affinity of most designs, we carried out a detailed examination of some designed structures. We found that favorable hydrogen bonds or hydrophobic interactions were introduced in the binder that had the lowest EvoEF2 binding score ( Figure 3B -C); the amino acid sequence of this binder was "EQEERIQQDKRKNEQEDKRYQRYGRGKGHQP". For this design, T27 was mutated to isoleucine ( Figure 3B ). In the wild-type structure, the threonine was enveloped by four hydrophobic residues on SARS-CoV-2 RBD (i.e. Y489, F456, Y473 and A475), but its hydroxyl group did not form any hydrogen bond with the hydroxyl group of either Y489 or Y473, and the mutation enhanced the favorable burial of nonpolar groups. The interface residue H34 was substituted for asparagine ( Figure 3B ), introducing a hydrogen bond to Y453 on SARS-CoV-2 RBD. Additionally, two mutations, F28Q and Q24E, simultaneously formed hydrogen bonds with the amide group of N487 from SARS-CoV-2 RBD ( Figure 3C ). Although the mutation D355H did not form hydrogen bonds with any residues from SARS-CoV-2, it simultaneously formed two hydrogen bonds with the hydroxyl group of Y41 and the main-chain carbonyl group of G45 on the peptide, which may help stabilize the loop region (a.a. 351-357).