The SARS-CoV-2 spike reversibly samples an open-trimer conformation exposing novel epitopes

Costello, Shawn M.; Shoemaker, Sophie R.; Hobbs, Helen T.; Nguyen, Annalee W.; Hsieh, Ching Lin; Maynard, Jennifer A.; McLellan, Jason S.; Pak, John E.; Marqusee, Susan

doi:10.1038/s41594-022-00735-5

Cited by 94 publications

(163 citation statements)

References 52 publications

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“…The authors found that spike samples four distinct conformational states forming an intermediate during ACE-2 recognition(54). Finally, hydrogen-deuterium exchange coupled with mass spectrometry revealed a spike conformation that interconverts slowly with the prefusion state and is more likely explained by an open trimer that exposes the S2 trimer interface(12). We experimentally compared the ancestral, D614G, beta, gamma, and delta variants to uncover their trimer stability and structural rigidity and understand spike evolution during the pandemic.…”

Section: Discussionmentioning

confidence: 99%

“…It leads to HR1-HR2 interactions bringing the viral envelope close to the cell's surface (2), and fusion occurs when host proteases promote the cleavage of the furin-like site. Weak hydrophobic interactions drive the trimer interface, unlocked during pre/postfusion conformational positioning (12). Virus evolution is an issue of concern during a pandemic.…”

Section: Introductionmentioning

confidence: 99%

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Uncovering the structural flexibility of SARS-CoV-2 glycoprotein spike variants

Arruda

Lima

Alvim

et al. 2022

Preprint

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The severe acute respiratory syndrome CoV-2 rapidly spread worldwide, causing a pandemic. After a period of evolutionary stasis, a set of SARS-CoV-2 mutations has arisen in the spike, the leading glycoprotein at the viral envelope and the primary antigenic candidate for vaccines against the 2019 CoV disease (COVID-19). Here, we present comparative biochemical data of the glycosylated full-length ancestral and D614G spike together with three other highly transmissible strains classified by the World Health Organization as variants of concern (VOC): beta, gamma, and delta. By showing that only D614G early variant has less hydrophobic surface exposure and trimer persistence at mid-temperatures, we place D614G with features that support a model of temporary fitness advantage for virus spillover worldwide. Further, during the SARS-CoV-2 adaptation, the spike accumulates alterations leading to less structural rigidity. The decreased trimer stability observed for the ancestral and the gamma strain and the presence of D614G uncoupled conformations mean higher ACE-2 affinities when compared to the beta and delta strains. Mapping the energetic landscape and flexibility of spike variants is necessary to improve vaccine development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Uncovering the structural flexibility of SARS-CoV-2 glycoprotein spike variants

Arruda

Lima

Alvim

et al. 2022

Preprint

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“…Unfortunately, the canonical version of the spike protein, the one present in vaccines, is one of the possible alternatives that presents the drawback of masking some important immunogenic epitopes conserved among coronaviruses in the RBD domain [24].…”

Section: Spike's Alternate Formsmentioning

confidence: 99%

mRNA COVID-19 Vaccines and Long-Lived Plasma Cells: A Complicated Relationship

Giannotta

2021

Vaccines

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mRNA COVID-19 vaccines have hegemonized the world market, and their administration to the population promises to stop the pandemic. However, the waning of the humoral immune response, which does not seem to last so many months after the completion of the vaccination program, has led us to study the molecular immunological mechanisms of waning immunity in the case of mRNA COVID-19 vaccines. We consulted the published scientific literature and from the few articles we found, we were convinced that there is an immunological memory problem after vaccination. Although mRNA vaccines have been demonstrated to induce antigen-specific memory B cells (MBCs) in the human population, there is no evidence that these vaccines induce the production of long-lived plasma cells (LLPCs), in a SARS-CoV-2 virus naïve population. This obstacle, in our point of view, is caused by the presence, in almost all subjects, of a cellular T and B cross-reactive memory produced during past exposures to the common cold coronaviruses. Due to this interference, it is difficult for a vaccination with the Spike protein alone, without adjuvants capable of prolonging the late phase of the generation of the immunological memory, to be able to determine the production of protective LLPCs. This would explain the possibility of previously and completely vaccinated subjects to become infected, already 4–6 months after the completion of the vaccination cycle.

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“…The S protein consists of conformationally adaptive amino (N)-terminal S1 subunit and structurally rigid carboxyl (C)-terminal S2 subunit, where S1 includes an N-terminal domain (NTD), the receptor-binding domain (RBD), and two structurally conserved subdomains SD1 and SD2 that coordinate protein response to binding partners and regulate the interactions with the host cell receptor ACE2. Conformational plasticity of the SARS-CoV-2 S protein are exemplified by spontaneous transitions from the closed state to the open state accompanied by large scale movements of the RBDs that can spontaneously fluctuate between "RBD-down" and "RBDup" positions, where binding to the host cell receptor ACE2 preferentially stabilizes the receptor-accessible "up" conformation [1][2][3][4][5][6][7][8][9][10][11][12]. The cryo-EM experimental tools have been deployed at unprecedented speed to characterize dynamic structural changes in the SARS-CoV-2 S protein, revealing a spectrum and atomic details of the prefusion S conformations that included various forms of the closed "RBD-down" state, "partially open" trimers with only one or two RBDs in the "up" conformation and "open" trimers with all three RBDs in the "up" position [5][6][7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

“…Conformational plasticity of the SARS-CoV-2 S protein are exemplified by spontaneous transitions from the closed state to the open state accompanied by large scale movements of the RBDs that can spontaneously fluctuate between "RBD-down" and "RBDup" positions, where binding to the host cell receptor ACE2 preferentially stabilizes the receptor-accessible "up" conformation [1][2][3][4][5][6][7][8][9][10][11][12]. The cryo-EM experimental tools have been deployed at unprecedented speed to characterize dynamic structural changes in the SARS-CoV-2 S protein, revealing a spectrum and atomic details of the prefusion S conformations that included various forms of the closed "RBD-down" state, "partially open" trimers with only one or two RBDs in the "up" conformation and "open" trimers with all three RBDs in the "up" position [5][6][7][8][9][10][11][12]. Structural changes that accompany SARS-CoV-2 S binding with the ACE2 host receptor demonstrated a well-orchestrated cascade of conformational transitions from a compact closed form weakened after furin cleavage to the partially open states and to the ACE2-bound open form [13,14].…”

Section: Introductionmentioning

confidence: 99%

Integrating Conformational Dynamics and Perturbation-Based Network Modeling for Mutational Profiling of Binding and Allostery in the SARS-CoV-2 Spike Variant Complexes with Antibodies: Balancing Local and Global Determinants of Mutational Escape Mechanisms

Verkhivker

Agajanian

Kassab

et al. 2022

Preprint

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In this study, we combined all-atom MD simulations, the ensemble-based mutational scanning of protein stability and binding, and perturbation-based network profiling of allosteric interactions in the SARS-Cov-2 Spike complexes with a panel of cross-reactive and ultra-potent single antibodies (B1-182.1 and A23-58.1) as well as antibody combinations (A19-61.1/B1-182.1 and A19-46.1/B1-182.1). Using this approach, we quantify local and global effects of mutations in the complexes, identify structural stability centers, characterize binding energy hotspots and predict the allosteric control points of long-range interactions and communications. Conformational dynamics and distance fluctuation analysis revealed the antibody-specific structural stability signatures of the spike complexes that can dictate the pattern of mutational escape. By employing an integrated analysis of conformational dynamics and binding energetics, we found that the potent antibodies that efficiently neutralize Omicron spike variant can form the dominant binding energy hotpots with the conserved stability centers in which mutations may be restricted by the requirements of the folding stability and binding to the host receptor. The results show that protein stability and binding energetics of the SARS-CoV-2 spike complexes with the panel of cross-reactive ultrapotent antibodies are tolerant to the constellation of Omicron mutations. A network-based perturbation approach for mutational profiling of allosteric residues potentials revealed how antibody binding can modulate allosteric interactions and identified allosteric control points that can form vulnerable sites for mutational escape. This study suggested a mechanism in which the pattern of specific escape mutants for ultrapotent antibodies may not be solely determined by the binding interaction changes but are driven by a complex balance and tradeoffs between different local and global factors including the impact of mutations on structural stability, binding strength, long-range interactions and fidelity of allosteric signaling.

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The SARS-CoV-2 spike reversibly samples an open-trimer conformation exposing novel epitopes

Cited by 94 publications

References 52 publications

Uncovering the structural flexibility of SARS-CoV-2 glycoprotein spike variants

Uncovering the structural flexibility of SARS-CoV-2 glycoprotein spike variants

mRNA COVID-19 Vaccines and Long-Lived Plasma Cells: A Complicated Relationship

Integrating Conformational Dynamics and Perturbation-Based Network Modeling for Mutational Profiling of Binding and Allostery in the SARS-CoV-2 Spike Variant Complexes with Antibodies: Balancing Local and Global Determinants of Mutational Escape Mechanisms

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