As the COVID-19 pandemic has progressed, new variants of the virus SARS-CoV-2 have emerged that are more infectious than the original form. The variants known as Alpha, Beta and Gamma have mutations in a protein on the virus’s surface that is vital for attaching to cells and infecting them. This protein, called Spike, carries out its role by binding to ACE2, a protein on the surface of human cells. Mutations on Spike are found on the region where it binds to ACE2.

The interaction between these two proteins appears to be important to the behaviour of SARS-CoV-2, but the impact of individual mutations in Spike is unknown. In addition, some people have different variants of ACE2 with mutations in the region that interacts with Spike, but it is not known whether this affects these people’s risk of contracting COVID-19.

To answer these questions, Barton et al. measured the precise effect of mutations in Spike and ACE2 on the strength of the interaction between the two proteins. The experiments showed that three of the five common Spike mutations in the Alpha, Beta and Gamma SARS-CoV-2 variants strengthened binding to ACE2. The two mutations that weakened binding were only found together with other mutations that strengthened binding. This meant that the Spike proteins in all three of these SARS-CoV-2 variants bind to ACE2 more strongly than the original form. The experiments also showed that two common variants of ACE2 also increased the strength of binding to Spike. Interestingly, one of these ACE2 variants reversed the effect of a specific SARS-CoV-2 mutation, suggesting that carriers would be resistant to SARS-CoV-2 variants with this mutation.

Identifying the precise effects of Spike mutations on ACE2 binding helps understand why new variants of SARS-CoV-2 spread more rapidly. This could help to identify concerning new variants before they spread widely and inform the response by health authorities. The finding that two common ACE2 variants bind more strongly to Spike suggests that people with these mutations could be more susceptible to SARS-CoV-2.

Since its identification in 2019, a coronavirus able to induce a severe acute respiratory syndrome in humans, SARS-CoV-2, has resulted in arguably the most severe infectious disease pandemic in 100 years. To date, more than 135 million people have been infected, resulting in the deaths from the resulting disease, COVID-19, of more than 3 million people (WHO, 2021), and measures introduced to control spread have had harmful social and economic impacts. Fortunately, effective vaccines have been developed, and a global vaccination programme is underway (Mahase, 2021). New SARS-CoV-2 variants of concern are emerging that are making containment of the pandemic more difficult, perhaps by increasing transmissibility of the virus (Davies et al., 2021; Korber et al., 2020; Volz et al., 2021b; Volz et al., 2021b; Washington et al., 2021) and/or its resistance to protective immunity induced by previous infection or vaccines (Darby and Hiscox, 2021; Dejnirattisai et al., 2021; Garcia-Beltran et al., 2021; Madhi et al., 2021a; Madhi et al., 2021b; Mahase, 2021; Volz et al., 2021b; Volz et al., 2021b).

The SARS-CoV-2 virus enters cells following an interaction between the Spike (S) protein on its surface with angiotensin-converting enzyme 2 (ACE2) on cell surfaces (V’kovski et al., 2021). The receptor-binding domain (RBD) of the Spike protein binds the membrane-distal portion of the ACE2 protein. The S protein forms a homotrimer, which is cleaved shortly after synthesis into two fragments that remain associated non-covalently: S1, which contains the RBD, and S2, which mediates membrane fusion following the binding of Spike to ACE2 (V’kovski et al., 2021). During the pandemic, mutations have appeared in the Spike protein that may increase transmissibility (Davies et al., 2021; Korber et al., 2020; Richard et al., 2021; Volz et al., 2021b; Volz et al., 2021b; Washington et al., 2021). One that emerged early in Europe, D614G, and quickly became dominant globally (Korber et al., 2020), increases the density of intact Spike trimer on the virus surface by preventing premature dissociation of S1 from S2 following cleavage (Zhang et al., 2021; Zhang et al., 2020). 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.

Prior infection by SARS-CoV-2 and current vaccines induce antibody responses to the Spike protein, and most neutralising antibodies appear to bind to the Spike RBD (Garcia-Beltran et al., 2021; Greaney et al., 2021a; Rogers et al., 2020). Some variants of concern have mutations in their RBD that confer resistance to neutralising antibodies (Darby and Hiscox, 2021; Dejnirattisai et al., 2021; Garcia-Beltran et al., 2021; Madhi et al., 2021a; Madhi et al., 2021b; Mahase, 2021). What is less clear is the precise effect of these mutations on the affinity and kinetics of the binding of RBD to ACE2. Previous studies of the interaction between the Spike RBD and ACE2 have produced a wide range of affinity and kinetic estimates under conditions (e.g. temperature) that are not always well defined (Lei et al., 2020; Shang et al., 2020; Supasa et al., 2021; Wrapp et al., 2020; Zhang et al., 2021; Zhang et al., 2020). Precise information is needed to assess the extent to which RBD mutations have been selected because they enhance ACE2 binding or facilitate immune evasion.

In this study, 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. Both mutations of ACE2 (S19P, K26R) and most of the mutations of RBD (N501Y, E484K, and S477N) enhanced the interaction, with one RBD mutation (N501Y) increasing the affinity by ~10-fold. Increased binding was the result of decreases in dissociation rate constants (N501Y, S477N) and/or increases in association rate constants (N501Y, E484K). Although 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 also present in both variants confer a net ~4-fold increase in the affinity of their RBDs for ACE2.

While our finding that the SARS-CoV-2 RBD binds ACE2 with an affinity of K_D 74 nM at 37°C is consistent with previous studies (K_D 6–133 nM) (Laffeber et al., 2021; Lei et al., 2020; Liu et al., 2021; Shang et al., 2020; Supasa et al., 2021; Wrapp et al., 2020; Zhang et al., 2021; Zhang et al., 2020), the rate constants that we measured (k_on 0.9 μM^–1.s^–1 and k_off 0.067 s^–1) were faster than all previous reports. One likely reason for this is that previous measurements were performed at a lower temperature, which almost always decreases rate constants. While some studies stated that binding constants were measured at 25°C (Laffeber et al., 2021; Zhang et al., 2020), most studies did not report the temperature, suggesting that they were performed at room temperature or the standard instrument temperature (20°C–25°C). A second likely reason is that previous kinetic studies were performed under conditions in which the rate of diffusion of soluble molecule to the sensor surface limits the association rate, and rebinding of dissociated molecules to the surface reduces the measured dissociation rate. These are known pitfalls of both techniques used in these studies, surface plasmon resonance (Myszka, 1997), and bilayer interferometry (Abdiche et al., 2008). In the present study, we avoided these issues by immobilising a very low level of ligand on the sensor surface. A third possible reason is that the proteins were aggregated, which can cause problems even when aggregates are a very minor contaminant (van der Merwe and Barclay, 1996). The presence of aggregates results in complex binding kinetics, which can be excluded if the simple 1:1 Langmuir binding model fits the kinetic data. While this was demonstrated in the present study, and some previous studies (Shang et al., 2020; Wrapp et al., 2020; Zhang et al., 2021), such fits were not shown in all studies, one of which reported more than 20-fold slower kinetics than reported here (Lei et al., 2020; Supasa et al., 2021).

The RBD mutations that we selected for analysis have all emerged independently and became dominant in a region at least once in different lineages, suggesting that they provide a selective advantage. Our finding that the N501Y, E484K, and S477N all increase the binding affinity of RBD for ACE2 raises the question as to whether this contributed to their selection. Several lines of evidence suggest that enhancing the Spike/ACE2 interaction would be advantageous for the virus. First, the virus has spread only very recently to humans from another mammalian host, providing insufficient time for optimisation of the affinity. Second, epidemiological studies have suggested that the Alpha variant, which has the N501Y mutation, has enhanced transmissibility (Volz et al., 2021a; Washington et al., 2021). Finally, a SARS-CoV-2 variant with the Spike mutation D614G, which increases its activity by stabilising it following furin cleavage (Zhang et al., 2021; Zhang et al., 2020), rapidly became dominant globally after it emerged (Korber et al., 2020; Volz et al., 2021b). Taken together, these findings suggest that the WT Spike/ACE2 interaction is limiting for transmission and that mutations that enhance it, including the N501Y, E484K, and S477N mutations, could provide a selective advantage by increasing transmissibility. This raises two questions. First, will other RBD mutations appear in SARS-CoV-2 which further enhance transmission? This seems likely, given that a large number of RBD mutations have been identified that increase the RBD/ACE2 affinity (Starr et al., 2020; Zahradník et al., 2021). Second, will combinations of existing mutations be selected because they further increase the affinity? While the appearance E484K, together with N501Y in three lineages (Alpha, Beta, and Gamma), supports this, it is also possible that E484K was selected because it disrupts antibody neutraliaation, as discussed below.

Our affinity and kinetic data on RBD variants are broadly consistent with some (Laffeber et al., 2021; Liu et al., 2021), but not all (Dejnirattisai et al., 2021; Zhou et al., 2021a), recent reports on the K417T/N, N501Y, and E484K variants. One caveat to our study is that we used monomeric forms of RBD and ACE2. The native Spike protein is a trimer and has several other domains, including the nearby N-teminal domain, and the native ACE2 protein can exist as a dimer (Yan et al., 2020). Because of these differences, our analysis may not detect the full effects of RBD and ACE2 mutations on the Spike/ACE2 interaction. A second caveat is that we have not examined the effect of these mutations on viral attachment to cells.

Studies of other enveloped viruses, including SARS-CoV, suggest that increases in affinity of viral ligands for their cellular receptors can increase cell infection and disease severity (Hasegawa et al., 2007; Li et al., 2005). One study found that increasing this affinity enabled the virus to infect cells with lower receptor surface density (Hasegawa et al., 2007). It follows that increases in affinity could increase the number of host tissues infected, which could increase the severity of disease (Cao and Li, 2020) and/or increase the viral load in the upper respiratory tract (Hoffmann et al., 2020; Wölfel et al., 2020), thereby increasing spread.

Another mechanism by which mutations of RBD could provide a selective advantage is through evasion of immune responses. This is supported by the observation that neutralising antibodies present in those infected by or vaccinated against SARS-CoV-2 primarily target the RBD (Garcia-Beltran et al., 2021; Greaney et al., 2021a; Rogers et al., 2020). Furthermore, two variants with RBD mutations that abrogate antibody neutralisation, Beta and Gamma, became dominant in regions with very high levels of prior SARS-CoV-2 infection (Cele et al., 2021; Dejnirattisai et al., 2021; Hoffmann et al., 2021; Sabino et al., 2021; Tegally et al., 2021; Zhou et al., 2021b). Both lineages include the N501Y mutation, but this appears to have modest effects on antibody neutralisation (Greaney et al., 2021a; Greaney et al., 2021b). In contrast, the E484K mutation, also present in both variants, potently disrupts antibody neutralisation (Greaney et al., 2021a; Greaney et al., 2021b). Our finding that the K417N/T mutations present in Beta and Gamma variants decrease the affinity of RBD for ACE2 suggests that they were selected because they facilitate immune escape. Indeed, mutations of K417 can block antibody neutralisation, albeit less effectively than E484K (Greaney et al., 2021a; Greaney et al., 2021b; Wang et al., 2021). It is notable that these affinity-reducing K417N/T mutations have only emerged together with mutations (N501Y and E484K) that increase the affinity of RBD for ACE2, suggesting a cooperative effect between mutations that enhance immune escape and mutations that increase affinity.

The effect of the increased affinity for SARS-CoV-2 Spike RBD of the K26R and S19P ACE2 mutants is less clear. The evidence summarised above that WT RBD/ACE2 binding is limiting for SARS-CoV-2 transmission, suggest that carriers of these ACE2 variants will be at greater risk of infection and/or severe disease. However, in contrast to SARS-CoV-2 RBD mutations, the effects of ACE2 variants are primarily relevant to the carriers of these mutations. A preliminary analysis (MacGowan et al., 2021) suggests that the carriers of the K26R ACE allele might be at increased risk of severe disease, but the findings did not reach statistical significance, and further studies are required.

The interaction that we identified between the RBD S477N and ACE2 S19P mutants highlights the importance of considering variation in the host population when studying the evolution of viral variants. In this case, the opposite effect of the RBD S477N mutation on its affinity for ACE2 S19P (decreased), compared with ACE2 WT (increased), suggests that this RBD variant may have a selective disadvantage amongst carriers of the ACE2 S19P variant, in contrast to those with ACE2 WT, where it appears to be advantageous. However, the low frequency of this variant means that this is unlikely to be important at a population level and will be difficult to detect.

It is noteworthy that the two most common ACE2 variants are in positions on ACE2 with no known functional activity. This raises the question as to whether these mutations are a remnant of historic adaption to pathogens that utilised this portion of ACE2. The fact that ACE2 S19P mutation is largely confined to African/African-American populations, suggests that it is more recent than K26R and/or selected by pathogen(s) confined to the African continent.

All data generated and analysed during this study are included in the manuscript and supporting files.

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Author details

1. Michael I Barton

   Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Project administration, Visualization, Writing – original draft, Writing – review and editing

   Contributed equally with

   Stuart A MacGowan

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9263-6481

2. Stuart A MacGowan

   School of Life Sciences, University of Dundee, Dundee, United Kingdom

   Contribution

   Conceptualization, Investigation, Visualization, Writing – review and editing

   Contributed equally with

   Michael I Barton

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4233-5071

3. Mikhail A Kutuzov

   Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

   Contribution

   Investigation, Methodology, Supervision

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3386-4350

4. Omer Dushek

   Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

   Contribution

   Conceptualization, Funding acquisition, Resources, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5847-5226

5. Geoffrey John Barton

   School of Life Sciences, University of Dundee, Dundee, United Kingdom

   Contribution

   Conceptualization, Resources, Supervision, Writing – review and editing

   For correspondence

   g.j.barton@dundee.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9014-5355

6. P Anton van der Merwe

   Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom

   Contribution

   Conceptualization, Formal analysis, Funding acquisition, Supervision, Writing – original draft, Writing – review and editing

   For correspondence

   anton.vandermerwe@path.ox.ac.uk

   Competing interests

   Own shares in BioNTech SE

   "This ORCID iD identifies the author of this article:" 0000-0001-9902-6590

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