Evolution of the SARS-CoV-2 spike protein in the
human host

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Recently emerged variants of SARS-CoV-2 contain in their surface spike glycoproteins
multiple substitutions associated with increased transmission and resistance to neutralising
antibodies. We have examined the structure and receptor binding properties of spike proteins
from the B.1.1.7 (Alpha) and B.1.351 (Beta) variants to better understand the evolution of the
virus in humans. Spikes of both variants have the same mutation, N501Y, in the receptorbinding
domains. This substitution confers tighter ACE2 binding, dependent on the common
earlier substitution, D614G. Each variant spike has acquired other key changes in structure
that likely impact virus pathogenesis. The spike from the Alpha variant is more stable against
disruption upon binding ACE2 receptor than all other spikes studied. This feature is linked to
the acquisition of a more basic substitution at the S1-S2 furin site (also observed for the
variants of concern Delta, Kappa, and Omicron) which allows for near-complete cleavage. In
the Beta variant spike, the presence of a new substitution, K417N (also observed in the
Omicron variant), in combination with the D614G, stabilises a more open spike trimer, a
conformation required for receptor binding. Our observations suggest ways these viruses
have evolved to achieve greater transmissibility in humans.