Effect of natural mutations of SARS-CoV-2 on spike structure, conformation and antigenicity

Gobeil, S.; Janowska, Katarzyna; McDowell, Shana; Mansouri, Katayoun; Parks, Robert; Stalls, Victoria; Kopp, Megan; Manne, Kartik; Saunders, Kevin O.; Edwards, Robert J.; Haynes, Barton F.; Henderson, Rory; Acharya, Priyamvada

doi:10.1101/2021.03.11.435037

Cited by 60 publications

(97 citation statements)

References 74 publications

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“…Thus, the RBD up in the UK system experiences higher fluctuations with respect to WT. This behavior might be responsible of the higher proportion of RBD up state particles observed in UK mutant Cryo-EM structures, due to a possible reduction of the transition barrier to the up state [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Altered Local Interactions and Long-Range Communications in UK Variant (B.1.1.7) Spike Glycoprotein

Borocci

Cerchia

Grottesi

et al. 2021

IJMS

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The COVID-19 pandemic is caused by SARS-CoV-2. Currently, most of the research efforts towards the development of vaccines and antibodies against SARS-CoV-2 were mainly focused on the spike (S) protein, which mediates virus entry into the host cell by binding to ACE2. As the virus SARS-CoV-2 continues to spread globally, variants have emerged, characterized by multiple mutations of the S glycoprotein. Herein, we employed microsecond-long molecular dynamics simulations to study the impact of the mutations of the S glycoprotein in SARS-CoV-2 Variant of Concern 202012/01 (B.1.1.7), termed the “UK variant”, in comparison with the wild type, with the aim to decipher the structural basis of the reported increased infectivity and virulence. The simulations provided insights on the different dynamics of UK and wild-type S glycoprotein, regarding in particular the Receptor Binding Domain (RBD). In addition, we investigated the role of glycans in modulating the conformational transitions of the RBD. The overall results showed that the UK mutant experiences higher flexibility in the RBD with respect to wild type; this behavior might be correlated with the increased transmission reported for this variant. Our work also adds useful structural information on antigenic “hotspots” and epitopes targeted by neutralizing antibodies.

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Section: Discussionmentioning

confidence: 99%

Altered Local Interactions and Long-Range Communications in UK Variant (B.1.1.7) Spike Glycoprotein

Borocci

Cerchia

Grottesi

et al. 2021

IJMS

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“…A ten-fold affinity gain is brought about by the N501Y mutation as Y501 interacts through a strong, aromatic stacking interaction with Y41 and forms two new hydrogen bonds with D38 and K353 in hAce2 [36]. Moreover, Y501 destabilises the RBD-down conformation, thereby adding to the D614G effect of more open RBDs [37]. An in-silico study revealed a key allosteric role of N501 together with E406, N439, and K417 as effector centres for long-range interactions running through S1, promoting its swinging motion after furin cleavage [18].…”

Section: The D614g Mutation In Spike Facilitates Sars-cov-2 Evolutionmentioning

confidence: 99%

“…Both the K417T and K417N mutations abolish this bond and are therefore predicted to have a lower hAce2 affinity while helping to evade neutralizing antibodies [56,57]. The main impact of the K417N mutation seems to be its ability to destabilize the RBD-down conformation, thereby increasing the propensity of the open configuration [37]. Whether this applies also to the K417T mutation is not yet clear, but it is likely, as K417 is a major site in the RBD with long-range, inter-molecular links throughout spike [18] (Table 2).…”

Section: The D614g Mutation In Spike Facilitates Sars-cov-2 Evolutionmentioning

confidence: 99%

“…Glutamate-484 (E484) forms a polar link with K31 in hAce2 despite its position at the outer rim of the RBD [9] (Figures 4 and 5). E484 also stabilizes the RBD-down conformation by contacting the N343-glycan and F490 in the neighbouring RBD [37]. Since both interactions are absent in the E484K mutant, the S1 movements favour the RBD-up conformation.…”

Section: The D614g Mutation In Spike Facilitates Sars-cov-2 Evolutionmentioning

confidence: 99%

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The Spike of Concern—The Novel Variants of SARS-CoV-2

Winger

Caspari

2021

Viruses

111

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The high sequence identity of the first SARS-CoV-2 samples collected in December 2019 at Wuhan did not foretell the emergence of novel variants in the United Kingdom, North and South America, India, or South Africa that drive the current waves of the pandemic. The viral spike receptor possesses two surface areas of high mutagenic plasticity: the supersite in its N-terminal domain (NTD) that is recognised by all anti-NTD antibodies and its receptor binding domain (RBD) where 17 residues make contact with the human Ace2 protein (angiotensin I converting enzyme 2) and many neutralising antibodies bind. While NTD mutations appear at first glance very diverse, they converge on the structure of the supersite. The mutations within the RBD, on the other hand, hone in on only a small number of key sites (K417, L452, E484, N501) that are allosteric control points enabling spike to escape neutralising antibodies while maintaining or even gaining Ace2-binding activity. The D614G mutation is the hallmark of all variants, as it promotes viral spread by increasing the number of open spike protomers in the homo-trimeric receptor complex. This review discusses the recent spike mutations as well as their evolution.

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“…Adaptive traits require close monitoring, particularly because they are likely to appear as increasingly prominent within SARS-CoV-2 strains under the current global vaccination efforts aiming at establishing herd immunity. Several studies focused on evaluating potential impact of mutations on the viral spread and antibody evasion (16,(21)(22)(23)(24)(25)(26)(27). Most investigations focused on the receptor binding domain (RBD) of the Spike, the immunodominant part of the protein (28) containing the ACE2-interacting interface.…”

Section: Introductionmentioning

confidence: 99%

Mutational hotspot in the SARS-CoV-2 Spike protein N-terminal domain conferring immune escape potential

Kubik

Arrigo

Bonet

et al. 2021

Preprint

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Global efforts are being taken to monitor the evolution of SARS-CoV-2, aiming at early identification of mutations with the potential of increasing viral infectivity or virulence. We report a striking increase in the frequency of recruitment of diverse substitutions at a critical residue (W152), positioned in the N-terminal domain (NTD) of the Spike protein, observed repeatedly across independent phylogenetic and geographical contexts. We investigate the impact these mutations might have on the evasion of neutralizing antibodies. Finally, we uncover that NTD is a region exhibiting particularly high frequency of mutation recruitments, suggesting an evolutionary path on which the virus maintains optimal efficiency of ACE2 binding combined with the flexibility facilitating the immune escape.

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Effect of natural mutations of SARS-CoV-2 on spike structure, conformation and antigenicity

Cited by 60 publications

References 74 publications

Altered Local Interactions and Long-Range Communications in UK Variant (B.1.1.7) Spike Glycoprotein

Altered Local Interactions and Long-Range Communications in UK Variant (B.1.1.7) Spike Glycoprotein

The Spike of Concern—The Novel Variants of SARS-CoV-2

Mutational hotspot in the SARS-CoV-2 Spike protein N-terminal domain conferring immune escape potential

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