Omicron SARS-CoV-2 mutations stabilize spike up-RBD conformation and lead to a non-RBM-binding monoclonal antibody escape

Zhao, Zhennan; Zhou, Jingya; Tian, Mingxiong; Huang, Min; Liu, Sheng; Xie, Yufeng; Han, Pu; Bai, C. H.; Han, Pengcheng; Zheng, Anqi; Fu, Lutang; Gao, Yuanzhu; Peng, Qi; Liu, Ying; Chai, Yan; Zhang, Zengyuan; Zhao, Xin; Song, Hao; Qi, Jianxun; Wang, Qihui; Wang, Peiyi; Gao, Lidong

doi:10.1038/s41467-022-32665-7

Cited by 99 publications

(85 citation statements)

References 72 publications

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“…This correlates with our high-speed AFM observations, showing less pronounced RBD opening and reduced angular and lateral RBD displacements, and is also consistent with recent EM studies reporting steric restrictions arising from a binding interface between two adjacent RBDs 51 , 52 , 55 , 56 that may lead to tight packing of the Omicron (B.1.1.529) RBDs 57 in the 3 RBD-down states and a slower transition of the Omicron (B.1.1.529) Spike from one-RBD-up to two-RBD-up or three-RBD-up conformations 51 . Furthermore, our data is also in line with a previous study demonstrating that a one-up RBD conformation of the Omicron (B.1.1.529) Spike is preserved after ACE2 binding, which is in stark contrast to other VOCs, where ACE2 binding of one RBD triggers the exposure of further up-RBDs 58 .…”

Section: Discussionsupporting

confidence: 93%

Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level

et al. 2022

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Recent waves of COVID-19 correlate with the emergence of the Delta and the Omicron variant. We report that the Spike trimer acts as a highly dynamic molecular caliper, thereby forming up to three tight bonds through its RBDs with ACE2 expressed on the cell surface. The Spike of both Delta and Omicron (B.1.1.529) Variant enhance and markedly prolong viral attachment to the host cell receptor ACE2, as opposed to the early Wuhan-1 isolate. Delta Spike shows rapid binding of all three Spike RBDs to three different ACE2 molecules with considerably increased bond lifetime when compared to the reference strain, thereby significantly amplifying avidity. Intriguingly, Omicron (B.1.1.529) Spike displays less multivalent bindings to ACE2 molecules, yet with a ten time longer bond lifetime than Delta. Delta and Omicron (B.1.1.529) Spike variants enhance and prolong viral attachment to the host, which likely not only increases the rate of viral uptake, but also enhances the resistance of the variants against host-cell detachment by shear forces such as airflow, mucus or blood flow. We uncover distinct binding mechanisms and strategies at single-molecule resolution, employed by circulating SARS-CoV-2 variants to enhance infectivity and viral transmission.

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Section: Discussionsupporting

confidence: 93%

Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level

et al. 2022

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“…In addition, from our alignments, we observed that the selected mutations remain consistent in all the subsequently emerged variants to date. Previous studies informed a stronger binding between Omicron Spike protein and ACE2 (23,56,72) and a reduction of binding between Omicron Spike protein and Abs (52,58,70). The predictive increased binding affinity caused by N501Y was consistent with these findings, while the other calculations may slightly differ.…”

Section: Discussionsupporting

confidence: 79%

“…Previous studies using cryo-EM structures and constant-pH Monte Carlo simulations showed that enhanced virulence could also be a consequence of an improved viral stability of the trimeric Spike in the open state with the better RBD availability to ACE2, rather than only through the alteration in the RBD-ACE2 interaction itself (10,67,68). Meanwhile, more research revealed that the Spike protein of Omicron is more likely to have one RBD-up conformation, not only maintaining the interaction with ACE2 but also restricting the recognition of antibody (69,70). In our in-silico work, we identified that three N to K mutations reported in Omicron and its subvariants may contribute to a mild preference of all the RBD-down conformation, compared to the prototype Spike protein.…”

Section: Discussionmentioning

confidence: 99%

A bias of Asparagine to Lysine mutations in SARS-CoV-2 outside the receptor binding domain affects protein flexibility

Boer¹,

Pan²,

Holien³

et al. 2022

Front. Immunol.

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IntroductionCOVID-19 pandemic has been threatening public health and economic development worldwide for over two years. Compared with the original SARS-CoV-2 strain reported in 2019, the Omicron variant (B.1.1.529.1) is more transmissible. This variant has 34 mutations in its Spike protein, 15 of which are present in the Receptor Binding Domain (RBD), facilitating viral internalization via binding to the angiotensin-converting enzyme 2 (ACE2) receptor on endothelial cells as well as promoting increased immune evasion capacity.MethodsHerein we compared SARS-CoV-2 proteins (including ORF3a, ORF7, ORF8, Nucleoprotein (N), membrane protein (M) and Spike (S) proteins) from multiple ancestral strains. We included the currently designated original Variant of Concern (VOC) Omicron, its subsequent emerged variants BA.1, BA2, BA3, BA.4, BA.5, the two currently emerging variants BQ.1 and BBX.1, and compared these with the previously circulating VOCs Alpha, Beta, Gamma, and Delta, to better understand the nature and potential impact of Omicron specific mutations.ResultsOnly in Omicron and its subvariants, a bias toward an Asparagine to Lysine (N to K) mutation was evident within the Spike protein, including regions outside the RBD domain, while none of the regions outside the Spike protein domain were characterized by this mutational bias. Computational structural analysis revealed that three of these specific mutations located in the central core region, contribute to a preference for the alteration of conformations of the Spike protein. Several mutations in the RBD which have circulated across most Omicron subvariants were also analysed, and these showed more potential for immune escape.ConclusionThis study emphasizes the importance of understanding how specific N to K mutations outside of the RBD region affect SARS-CoV-2 conformational changes and the need for neutralizing antibodies for Omicron to target a subset of conformationally dependent B cell epitopes.

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“…The Spike interacts with its ACE2 receptor in its “up” conformation [ 46 ]. However, the Spike trimer of Omicron BA.1 and subvariant BA.2 was reported to assume more the RBD “down” conformation that is stabilised by a strong network of inter-protomer contacts leading to its higher thermostability [ 47 , 48 ]. Therefore, we studied the sensitivity of the Spike subvariants to conformational changes in response to ACE2.…”

Section: Resultsmentioning

confidence: 99%

Temperature Influences the Interaction between SARS-CoV-2 Spike from Omicron Subvariants and Human ACE2

Gong

Ding

Benlarbi

et al. 2022

Viruses

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SARS-CoV-2 continues to infect millions of people worldwide. The subvariants arising from the variant-of-concern (VOC) Omicron include BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4, and BA.5. All possess multiple mutations in their Spike glycoprotein, notably in its immunogenic receptor-binding domain (RBD), and present enhanced viral transmission. The highly mutated Spike glycoproteins from these subvariants present different degrees of resistance to recognition and cross-neutralisation by plasma from previously infected and/or vaccinated individuals. We have recently shown that the temperature affects the interaction between the Spike and its receptor, the angiotensin converting enzyme 2 (ACE2). The affinity of RBD for ACE2 is significantly increased at lower temperatures. However, whether this is also observed with the Spike of Omicron and sub-lineages is not known. Here we show that, similar to other variants, Spikes from Omicron sub-lineages bind better the ACE2 receptor at lower temperatures. Whether this translates into enhanced transmission during the fall and winter seasons remains to be determined.

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Omicron SARS-CoV-2 mutations stabilize spike up-RBD conformation and lead to a non-RBM-binding monoclonal antibody escape

Cited by 99 publications

References 72 publications

Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level

Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level

A bias of Asparagine to Lysine mutations in SARS-CoV-2 outside the receptor binding domain affects protein flexibility

Temperature Influences the Interaction between SARS-CoV-2 Spike from Omicron Subvariants and Human ACE2

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