Computational epitope map of SARS-CoV-2 spike protein

Sikora, Mateusz; Bülow, Sören von; Blanc, Florian; Gecht, Michael; Covino, Roberto; Hummer, Gerhard

doi:10.1371/journal.pcbi.1008790

Cited by 126 publications

(163 citation statements)

References 55 publications

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“…However, the shorter timescale of these simulations prevented the authors from capturing the opening process at all. With our milliseconds of sampling, we successfully 35,40,41 captured this rare event for both glycosylated and unglycosylated S and found that glycosylation slightly increases the population of the open state, but the difference between glycosylated and unglycosylated S is smaller than that between different spike variants (Supplementary Fig. 1).…”

Section: Extreme Spike Opening Reveals Cryptic Epitopesmentioning

confidence: 97%

SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome

et al. 2021

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SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression and replication that depend on the structure and dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate 0.1 seconds of the viral proteome. Our adaptive sampling simulations predict dramatic opening of the apo spike complex, far beyond that seen experimentally, explaining and predicting the existence of 'cryptic' epitopes. Different spike variants modulate the probabilities of open versus closed structures, balancing receptor binding and immune evasion. We also discover dramatic conformational changes across the proteome, which reveal over 50 'cryptic' pockets that expand targeting options for the design of antivirals. All data and models are freely available online, providing a quantitative structural atlas.

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Section: Extreme Spike Opening Reveals Cryptic Epitopesmentioning

confidence: 97%

SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome

et al. 2021

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“…The structural change of the complexes was easily monitored over simulation trajectories. 37,53,54 The backbone root-meansquare deviation (RMSD) of the complexes suggested that systems mostly reached equilibrium states after 40 ns of MD simulations (Figures S1-S2 of the Supporting Information). Structural analyses were then carried out over equilibrium intervals of S protein + FAb complexes.…”

Section: Resultsmentioning

confidence: 99%

501Y.V2 Spike Protein Resists the Antibody in Atomistic Simulations

Ngo

2021

Preprint

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<div> <p><a>SARS-CoV-2 Spike (S) protein is a major biological target for COVID-19 vaccine design. Unfortunately, recent reports indicated that Spike (S) protein mutations can lead to antibody resistance. </a>However, understanding the process is limited, especially at the atomic scale. The structural change of S protein and neutralizing antibody fragment (FAb) complexes was thus probed using molecular dynamics (MD) simulations. In particular, backbone RMSD of the 501Y.V2 complex was significantly larger than that of the WT implying a large structural change of the mutation system. Moreover, the mean of , CCS, and SASA are almost the same when compared two complexes, but the distribution of these values are absolutely different. Furthermore, the free energy landscape of the complexes was significantly changed when the 501Y.V2 variant was induced. The binding pose between S protein and FAb was thus altered. The FAb-binding affinity to S protein was thus reduced due to revealing over steered-MD (SMD) simulations. The observation is in good agreement with the respective experiment that the 501Y.V2 SARS-CoV-2 variant can escape from neutralizing antibody (NAb).</p> </div>

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“…played an important role in shaping up our understanding of the dynamics and function of SARS-CoV-2 glycoproteins. [66][67][68][69][70][71][72][73][74][75][76] All-atom MD simulations of the full-length SARS-CoV-2 S glycoprotein embedded in the viral membrane, with a complete glycosylation profile were first reported by Amaro and colleagues, providing the unprecedented level of details and significant structural insights about functional S conformations. 69 A "bottom-up" coarse-grained (CG) model of the SARS-CoV-2 virion integrated data from cryo-EM, x-ray crystallography, and computational predictions to build molecular models of structural SARS-CoV-2 proteins assemble a complete virion model.…”

Section: Computer Simulations and Protein Modelingmentioning

confidence: 99%

Atomistic Simulations and Deep Mutational Scanning of Protein Stability and Binding Interactions in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Molecular Determinants of Mutational Escape Mechanisms

Verkhivker

Agajanian

et al. 2021

Preprint

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Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against SARS-CoV-2 virus and resilience against mutational escape. In this work, we combined atomistic simulations and conformational dynamics analysis with the ensemble-based mutational profiling of binding interactions for a diverse panel of SARS-CoV-2 spike complexes with nanobodies. Using this computational toolkit we identified dynamic signatures and binding affinity fingerprints for the SARS-CoV-2 spike protein complexes with nanobodies Nb6 and Nb20, VHH E, a pair combination VHH E+U, a biparatopic nanobody VHH VE, and a combination of CC12.3 antibody and VHH V/W nanobodies. Through ensemble-based deep mutational profiling of stability and binding affinities, we identify critical hotspots and characterize molecular mechanisms of SARS-CoV-2 spike protein binding with single ultra-potent nanobodies, nanobody cocktails and biparatopic nanobodies. By quantifying dynamic and energetic determinants of the SARS-CoV-2 S binding with nanobodies, we also examine the effects of circulating variants and escaping mutations. We found that mutational escape mechanisms may be controlled through structurally and energetically adaptable binding hotspots located in the host receptor-accessible binding epitope that are dynamically coupled to the stability centers in the distant epitope targeted by VHH U/V/W nanobodies. The results of this study suggested a mechanism in which through cooperative dynamic changes, nanobody combinations and biparatopic nanobody can modulate the global protein response and induce the increased resilience to common escape mutants.

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Computational epitope map of SARS-CoV-2 spike protein

Cited by 126 publications

References 55 publications

SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome

SARS-CoV-2 simulations go exascale to predict dramatic spike opening and cryptic pockets across the proteome

501Y.V2 Spike Protein Resists the Antibody in Atomistic Simulations

Atomistic Simulations and Deep Mutational Scanning of Protein Stability and Binding Interactions in the SARS-CoV-2 Spike Protein Complexes with Nanobodies: Molecular Determinants of Mutational Escape Mechanisms

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