Single point mutations can potentially enhance infectivity of SARS-CoV-2 revealed by in silico affinity maturation and SPR assay

Abstract

The RBD (receptor binding domain) of the SARS-CoV-2 virus S (spike) protein mediates the viral cell attachment and serves as a promising target for therapeutics development. Mutations on the S-RBD may alter its affinity to cell receptor and affect the potency of vaccines and antibodies. Here we used an in-silico approach to predict how mutations on RBD affect its binding affinity to hACE2 (human angiotensin-converting enzyme2). The effect of all single point mutations on the interface was predicted. SPR assay result shows that 6 out of 9 selected mutations can strengthen binding affinity. Our prediction has reasonable agreement with the previous deep mutational scan results and recently reported mutants. Our work demonstrated in silico method as a powerful tool to forecast more powerful virus mutants, which will significantly benefit for the development of broadly neutralizing vaccine and antibody.

Neutralising antibody escape of SARS‐CoV‐2 spike protein: Risk assessment for antibody‐based Covid‐19 therapeutics and vaccines

“…Alternatively, in silico modelling can be used. The ddG represents the difference in protein‐protein affinity upon mutation: it can be measured using the Rosetta Flex ddG method, and validated using surface plasmon resonance 180 . GRID‐based pharmacophore model has been used to identify mutations in both Spike (N439K, L455F, G446V, G476S, S477I, S477N, E484Q and N501Y) and ACE2 that reciprocally affect binding and are recognised in sequence repositories 181 …”

Computational modelling of potentially emerging SARS-CoV-2 spike protein RBDs mutations with higher binding affinity towards ACE2: A structural modelling study

“…The researchers found N501T SARS-CoV-2 variants in 11/11 experimentally infected ferrets, with a rising fraction of the virome demonstrated over time, indicating significant positive selection in ferrets [ 50 ]. On the other hand, the N501V are reported to stabilize the interactions [ 51 ]. Hence, our results are corroborated with these previous findings as N501T shows strong positive fitness while the N501V failed in the experimental validation, which is also reported as a weak binding mutation.…”

Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine Escape

“…Alternative approaches have been reviewed (41)(42)(43)(44), but the minimal approach pursued maximizes the breadth of candidate mutations considered and is able to recapitulate experimental results. As an alternative to constructing the variant ensembles starting with the crystal structure, we considered starting with the conformational ensemble constructed for the WT and applying a reduced protocol of iterative minimization and repacking for conformational optimization.…”