Computational design of SARS-CoV-2 peptide binders with better predicted binding affinities than human ACE2 receptor

Abstract

SARS-CoV-2 is coronavirus causing COVID-19 pandemic. To enter human cells, receptor binding domain of S1 subunit of SARS-CoV-2 (SARS-CoV-2-RBD) binds to peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) receptor. Employing peptides to inhibit binding between SARS-CoV-2-RBD and ACE2-PD is a therapeutic solution for COVID-19. Previous experimental study found that 23-mer peptide (SBP1) bound to SARS-CoV-2-RBD with lower affinity than ACE2. To increase SBP1 affinity, our previous study used residues 21–45 of α1 helix of ACE2-PD (SPB25) to design peptides with predicted affinity better than SBP1 and SPB25 by increasing interactions of residues that do not form favorable interactions with SARS-CoV-2-RBD. To design SPB25 with better affinity than ACE2, we employed computational protein design to increase interactions of residues reported to form favorable interactions with SARS-CoV-2-RBD and combine newly designed mutations with the best single mutations from our previous study. Molecular dynamics show that predicted binding affinities of three peptides (SPB25Q22R, SPB25F8R/K11W/L25R and SPB25F8R/K11F/Q22R/L25R) are better than ACE2. Moreover, their predicted stabilities may be slightly higher than SBP1 as suggested by their helicities. This study developed an approach to design SARS-CoV-2 peptide binders with predicted binding affinities better than ACE2. These designed peptides are promising candidates as SARS-CoV-2 inhibitors.

Smaller, Stronger, More Stable: Peptide Variants of a SARS-CoV-2 Neutralizing Miniprotein

“…Therefore, current research is also focused on developing alternative, smaller molecules capable of interfering with the interaction of the SARS-CoV-2 spike protein with cellular ACE2 [ 12 , 13 , 14 , 15 ]. Over the past two years, a range of studies have reported the computational design of smaller proteins or peptides, either based on the structure of the two N-terminal α-helices of ACE2, through which it contacts the receptor binding domain (RBD) of the SARS-CoV-2 spike protein [ 16 , 17 , 18 , 19 ], or through de novo design based on the RBD structure [ 19 , 20 , 21 ]. In a mechanism similar to antibodies, such peptides and miniproteins can be expected to bind to RBD, preventing its interaction with ACE2, thus blocking infection.…”

Prediction of infectivity of SARS-CoV2: Mathematical model with analysis of docking simulation for spike proteins and angiotensin-converting enzyme 2

“…In previous research, only the RBD domain of the spike protein was used in the analysis of binding affinity with ACE2: no MD analysis of the structure optimization ( Celik et al, 2022 ; Gan et al, 2021 ; Shah and Woo, 2021 ; Sitthiyotha and Chunsrivirot, 2021 ; Tragni et al, 2022 ) and/or local optimization of only the RBD domain of the spike protein ( Celik et al, 2022 ; Gan et al, 2021 ; Kumar et al, 2022 ; Shah and Woo, 2021 ; Sitthiyotha and Chunsrivirot, 2021 ; Tragni et al, 2022 ; Xue et al, 2021 ). However, we chose the three-dimensional structure of the complete trimeric spike protein (PDB ID: 6ZGG ) in homology modeling in this research.…”

Prediction of infectivity of SARS-CoV2: Mathematical model with analysis of docking simulation for spike proteins and angiotensin-converting enzyme 2

“…In other previous research, only RBD domain of spike protein were used for the analysis of binding affinity with ACE2 as below: no MD analysis for the structure optimization [22][23][24][25][26] and/or local optimization of only RBD domain [22][23][24][25][26][27][28] of spike protein. However, we choose 3-D structure of whole trimer spike protein (PDB ID: 6ZGG) for homology modeling in this research.…”

“…In previous research, only the RBD domain of the spike protein was used in the analysis of binding affinity with ACE2: no MD analysis of the structure optimization [22][23][24][25][26] and/or local optimization of only the RBD domain [22][23][24][25][26][27][28] of the spike protein.…”