Enhancement of SARS-CoV-2 Receptor Binding Domain -CR3022 Human Antibody Binding Affinity via In silico Engineering Approach

Introduction: The angiotensin-converting enzyme 2 (ACE2) is the effective primary receptor for SARS-CoV-2. The interaction between ACE2 and the spike protein of the virus is the crucial step for virus entry into the target cells. ACE2 receptor can be blocked by neutralizing antibodies (nAbs) such as CR3022 which targets the virus receptor-binding site. Enhancing the binding affinity between CR3022 and ACE2 would lead to a more efficient blockade of virus entry. Methods:  In this regard, the amino acids with central roles in the binding affinity of CR3022 antibody to spike protein were substituted. The best mutations to increase the affinity of antibodies were also selected based on protein-protein docking and molecular dynamics simulations. Result: The variants 45 (H:30I/G, H:55D/F, H: 103S/Y, L:59T/F, L:98Y/A), 60(H:31T/D, H:55D/E,  H:103S/Y, L:59T/D, L:98Y/F), 67(H:30I/G, H:55D/F, H:103S/Y, L:56 W/L, L:59T/Y, L:61E/G), 69(H:31T/D,  H:55D/F,   H:103S/Y, L:59T/F, L:98Y/A), and 71(H: 31T/D, H:55D/F, H:103S/Y) with respective binding affinities of -167.3, -167.5, -161.6, -173.0, and -169.8 Kcal/mol had higher binding affinities against the RBD of the SARS-CoV2 spike protein compared to the wild-type Ab. Conclusion: The engineered antibodies with higher binding affinities against the target protein can improve specificity and sensitivity. Thus, a more successful blockade of the ACE2 is achieved, resulting in a better therapeutic outcome. In silico studies can pave the way for designing these engineered molecules avoiding the economic and ethical challenges.

Enhancement of SARS-CoV-2 Receptor Binding Domain -CR3022 Human Antibody Binding Affinity via In silico Engineering Approach Keywords:

Coronavirus , SARS-COV-2 , Antibody , Bioinformatics , Affinity maturation