Abstract
SARS-CoV-2 is responsible for COVID-19 pandemic, causing large numbers of cases and deaths. It initiates entry into human cells by binding to the peptidase domain of angiotensin-converting enzyme 2 (ACE2) receptor via its receptor binding domain of S1 subunit of spike protein (SARS-CoV-2-RBD). Employing neutralizing antibodies to prevent binding between SARS-CoV-2-RBD and ACE2 is an effective COVID-19 therapeutic solution. Previous studies found that CC12.3 is a highly potent neutralizing antibody that was isolated from a SARS-CoV-2 infected patient, and its Fab fragment (Fab CC12.3) bound to SARS-CoV-2-RBD with comparable binding affinity to ACE2. To enhance its binding affinity, we employed computational protein design to redesign all CDRs of Fab CC12.3 and molecular dynamics (MD) to validate their predicted binding affinities by the MM-GBSA method. MD results show that the predicted binding affinities of the three best designed Fabs CC12.3 (CC12.3-D02, CC12.3-D05, and CC12.3-D08) are better than those of Fab CC12.3 and ACE2. Additionally, our results suggest that enhanced binding affinities of CC12.3-D02, CC12.3-D05, and CC12.3-D08 are caused by increased SARS-CoV-2-RBD binding interactions of CDRs L1 and L3. This study redesigned neutralizing antibodies with better predicted binding affinities to SARS-CoV-2-RBD than Fab CC12.3 and ACE2. They are promising candidates as neutralizing antibodies against SARS-CoV-2.
Highlights
The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused large numbers of morbidity and m ortality[1,2,3,4,5]
The previous experimental study found that the Fab fragment of CC12.3 (Fab CC12.3), which was isolated from a SARS-CoV-2 infected patient, was among the top four highly potent neutralizing antibodies
Fab CC12.3 bound to SARS-CoV-2-receptor-binding domain (RBD) with Kd of 14 nM30, which is comparable to Kd of angiotensin-converting enzyme 2 (ACE2) binding to SARS-CoV-2-RBD (14.7 nM)[31], and it bound to an epitope that overlaps with ACE2-binding site
Summary
The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused large numbers of morbidity and m ortality[1,2,3,4,5]. Neutralizing antibodies is an effective therapeutic solution for COVID-19 as they can effectively inhibit viral infection of human cells by blocking the binding interactions between SARS-CoV-2-RBD and ACE2-PD. Jiao Chen et al performed virtual scanning mutageneses and MD to improve the binding affinity to SARS-CoV-2RBD of P2B-2F6, which was isolated from single B cells of SARS-CoV-2 infected patients. They found that two P2B-2F6 mutants (H:V106R and H:V106R/H:P107Y) have higher binding affinities to SARS-CoV-2-RBD than P2B-2F6 and other mutants, suggesting that these two mutants might have higher neutralizing activity against SARS-CoV-2 than P2B-2F68. Their experimental results show that all designed antibodies are highly stable and bound to their targets with nanomolar affinities[34]
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