Abstract
The interaction between the SARS-CoV-2 virus Spike protein receptor binding domain (RBD) and the ACE2 cell surface protein is required for viral infection of cells. Mutations in the RBD are present in SARS-CoV-2 variants of concern that have emerged independently worldwide. For example, the B.1.1.7 lineage has a mutation (N501Y) in its Spike RBD that enhances binding to ACE2. There are also ACE2 alleles in humans with mutations in the RBD binding site. Here we perform a detailed affinity and kinetics analysis of the effect of five common RBD mutations (K417N, K417T, N501Y, E484K, and S477N) and two common ACE2 mutations (S19P and K26R) on the RBD/ACE2 interaction. We analysed the effects of individual RBD mutations and combinations found in new SARS-CoV-2 Alpha (B.1.1.7), Beta (B.1.351), and Gamma (P1) variants. Most of these mutations increased the affinity of the RBD/ACE2 interaction. The exceptions were mutations K417N/T, which decreased the affinity. Taken together with other studies, our results suggest that the N501Y and S477N mutations enhance transmission primarily by enhancing binding, the K417N/T mutations facilitate immune escape, and the E484K mutation enhances binding and immune escape.
Highlights
Since its identification in 2019, a coronavirus able to induce a severe acute respiratory syndrome in humans, SARS-C oV-2, has resulted in arguably the most severe infectious disease pandemic in 100 years
We will refer to the common angiotensin-converting enzyme 2 (ACE2) allele and receptor-binding domain (RBD) of the original SARS-C oV-2 strain sequenced in Wuhan as wild type (WT)
We examined the effect on ACE2 binding of combinations of RBD mutations, including combinations present in VOC-202102–02, a subset of the Alpha lineage (N501Y) with the E484K mutation (“SARS-CoV-2 Variants of concern and variants under investigation – GOV.UK,” 2021), and the Beta and Gamma variants (Figure 3C, Table 1)
Summary
Since its identification in 2019, a coronavirus able to induce a severe acute respiratory syndrome in humans, SARS-C oV-2 , has resulted in arguably the most severe infectious disease pandemic in 100 years. A later mutation, N501Y, which has appeared in multiple lineages, lies within the RBD, and increases its affinity for ACE2 (Starr et al, 2020; Supasa et al, 2021) These findings suggest that mutations that directly or indirectly enhance Spike binding to ACE2 may increase transmissibility. We undertook a detailed affinity and kinetic analysis of the interaction between Spike RBD and ACE2 at a physiological temperature (37 °C), taking care to avoid common pitfalls. We used this optimised approach to analyse the effect of important common mutations identified in variants of RBD and ACE2. The K417N/T mutations found in the South African (B.1.351) and Brazilian (P.1) variants both decreased the affinity, the affinity-enhancing N501Y and E484K mutations that are present in both variants confer a net ~4 -fold increase in the affinity of their RBDs for ACE2
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