Abstract
New globally circulating SARS-CoV-2 strains are causing concern about evolution of virus transmissibility, fitness and immune evasion mechanisms. A variant emerging from the United Kingdom called SARS-CoV-2 VUI 202012/01, or B.1.1.7, is thought to exhibit increased transmissibility that results from replication 4–10 times faster than the original Wuhan virus (Wuhan-Hu-1). Although this property is suspected to result from a specific mutation in the spike glycoprotein, D614G, there are 9 mutations that distinguish the UK variant B.1.1.7 from Wuhan-Hu-1 yet to be evaluated for functional effects. We asked if mutated positions fixed in UK variant B.1.1.7 may be involved in the virus life cycle, or evasion of the immune response, by modeling the UK variant spike protein and conducting structural analysis of mutations on the spike glycoprotein trimer (protomer) complexed to ACE2. Importantly, 4 out of 9 differences between the UK variant B.1.1.7 and Wuhan-Hu-1 spike protein alter direct intermolecular interactions. N501Y increased affinity between the spike protein and ACE2. The mutations at A570D, D614G and S982A reduced contact between individual chains of the trimeric spike protomer, potentially enhancing cleavage into S1 and S2 subunits, dynamic structural rearrangement and host cell fusion mechanisms. These data suggest that combined characteristics of mutations unique to UK variant B.1.1.7 enable high affinity binding to ACE2 and enhanced replication properties. The D614G mutation, associated with enhanced virus transmissibility, opens a potentially druggable structural pocket at the interface between spike glycoprotein subunits S1 and S2.
Highlights
There are 9 sites that differ between SARS-CoV-2 spike glycoproteins from the original Wuhan strain (WuhanHu-1) and UK variant B.1.1.7 [1] (Figure 1, Table 1)
Most substitutions in the spike protein that distinguish UK variant B.1.1.7 are located at sites of intermolecular interaction (4 out of 7 substitutions)
N501Y was modeled based on the cryoEM structure of the WuhanHu-1 spike protein/ACE2 complex [3] (Figure 2A, PDB 6M17), indicating that the gain in affinity likely results from aromatic interactions (π stacking) between Tyr501 and Tyr41 of ACE2 (Figure 2B)
Summary
There are 9 sites that differ between SARS-CoV-2 spike glycoproteins from the original Wuhan strain (WuhanHu-1) and UK variant B.1.1.7 [1] (Figure 1, Table 1). Most substitutions in the spike protein that distinguish UK variant B.1.1.7 are located at sites of intermolecular interaction (4 out of 7 substitutions). 3 mutations in the spike protein that distinguish UK variant B.1.1.7 are located at interfaces between subunits of the trimeric protomer.
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