Anticipating dangerous COVID-19 variants

Researchers at New York University and New York University Abu Dhabi used structural modelling to predict how mutations in the spike protein of SARS-CoV-2 and its target, the human ACE2 receptor (hACE2), would affect their binding affinity. This binding enables the virus to enter the host cell, making it a key step in the life cycle and an important factor affecting how infectious the virus is.

To confirm the accuracy of the structural model, they first predicted the binding affinities of spike-hACE2 combinations that have already been measured. Next, they used it to analyse 731 possible combinations of variants in the spike protein and hACE2. Only 31 combinations (4% of the total) resulted in complexes with a high binding affinity. Of these, 29 involved a mutation in both the spike protein and the hACE2 receptor. 

Next, the team identified five possible spike protein mutations that had a high binding affinity with individual ACE2 variants and when averaged across all the hACE2 variants. These “high-confidence, high-affinity” variants are notable as candidates with potential high infectivity. According to the analysis, two of these five could avoid neutralizing antibodies, highlighting the need to monitor for them.

The research also revealed a potentially dangerous combination to watch out for. “Our study identified the as yet unobserved variant S477N+E484K+N501Y that has a very high affinity and is capable of escaping some antibodies through the widespread E484K mutation,” says Hin Hark Gan, lead author of the study. “It is a novel combination of circulating variants. A high priority should be given to surveillance of this variant.”

Finally, the researchers investigated the basis for the rapid spread of several currently circulating variants. According to their analysis, some of the variants spread more quickly because they have a higher binding affinity, leading to greater infectivity. Others have a normal binding affinity but nevertheless spread quickly because they can evade antibodies, and some variants combine increased affinity with antibody evasion.

This research not only helps explain the rapid spread of certain variants but also provides a way to anticipate dangerous mutations in order to guide surveillance efforts and vaccine development. “Ongoing surveillance is essential to detect emerging infectious variants. The spike protein alone has around 5,000 variants, and the biological and health implications of the vast majority of them are unknown,” says Gan.

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