Conformational Ensembles of Non-Coding Elements in the SARS-CoV-2 Genome from Molecular Dynamics Simulations

Bottaro, Sandro; Bussi, Giovanni; Lindorff‐Larsen, Kresten

doi:10.1101/2020.12.11.421784

Cited by 3 publications

(2 citation statements)

References 82 publications

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“…However, in the secondary structure prediction using CentroidFold [ 61 ] and the reference sequence, these base pairs were predicted to exist in more than 92% of the ensemble. Furthermore, a recent study [ 59 ] showed that, even with a rigorous extended ensemble simulation, the hairpin structure remained intact. Given these results, the drawback of structural restraints to SL1 is expected to be minimal.…”

Section: Resultsmentioning

confidence: 99%

“…First, as we explained in "Convergence of the extended ensemble simulation", even though the current simulation uses the extended ensemble method, it is difficult to achieve full convergence. Sampling RNA structures are generally considered difficult even with the small system size, [55][56][57][58][59] and so does sampling the protein-RNA interaction. Given the length of IDR and the size of RNAs, the convergence of the simulation may be beyond the capability of the current computational resources.…”

Section: Limitations Of This Studymentioning

confidence: 99%

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Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex

et al. 2022

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Nonstructural protein 1 (nsp1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 180-residue protein that blocks translation of host mRNAs in SARS-CoV-2-infected cells. Although it is known that SARS-CoV-2’s own RNA evades nsp1’s host translation shutoff, the molecular mechanism underlying the evasion was poorly understood. We performed an extended ensemble molecular dynamics simulation to investigate the mechanism of the viral RNA evasion. Simulation results suggested that the stem loop structure of the SARS-CoV-2 RNA 5’-untranslated region (SL1) binds to both nsp1’s N-terminal globular region and intrinsically disordered region. The consistency of the results was assessed by modeling nsp1-40S ribosome structure based on reported nsp1 experiments, including the X-ray crystallographic structure analysis, the cryo-EM electron density map, and cross-linking experiments. The SL1 binding region predicted from the simulation was open to the solvent, yet the ribosome could interact with SL1. Cluster analysis of the binding mode and detailed analysis of the binding poses suggest residues Arg124, Lys47, Arg43, and Asn126 may be involved in the SL1 recognition mechanism, consistent with the existing mutational analysis.

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Section: Resultsmentioning

confidence: 99%

Section: Limitations Of This Studymentioning

confidence: 99%

Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex

et al. 2022

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Modeling the SARS-CoV-2 nsp1–5’-UTR complex via extended ensemble simulations

Sakuraba

Xie

Kasahara

et al. 2021

Preprint

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Nonstructural protein 1 (nsp1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a 180-residue protein that blocks the translation of SARS-CoV-2 infected cells. Although it has been known that SARS-CoV-2's own RNA evades an nsp1's host translation shutoff, its molecular mechanism has been poorly understood. We performed an extended ensemble molecular dynamics simulation to investigate the mechanism of viral RNA evasion. Simulation results showed that the stem loop structure of SARS-CoV-2 RNA 5'-untranslated region is recognized by both nsp1's globular region and intrinsically disordered region. The recognition presumably enables selectively translating the viral RNAs. A cluster analysis of the binding mode and a detailed analysis of the binding poses were performed, and we identified a few important residues involved in the SL1 recognition mechanism. The simulation results implied that nsp1 C-terminal helices are lifted from the 40S ribosome upon the binding of SL1 to the nsp1, reenabling the translation blocked by the C-terminal helices.

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RNA triplex structures revealed by WAXS-driven MD simulations

Chen

Kırmızıaltın

et al. 2022

Preprint

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RNA triple helices are commonly observed tertiary motifs that are increasingly associated with critical biological functions, including signal transduction. Because the recognition of their biological importance is relatively recent, their full range of structures and function has not yet been elucidated. The integration of solution wide-angle X-ray scattering (WAXS) with data-driven molecular dynamics (MD) simulations, described here, provides a new way to capture the structures of major-groove RNA triplexes that evade crystallographic characterization. This method yields excellent agreement between measured and computed WAXS profiles, and allows for an atomically detailed visualization of these motifs. Using correlation maps, the relationship between well-defined features in the scattering profiles and real space characteristics of RNA molecules is easily defined, including the subtle conformational variations in the double-stranded RNA upon the incorporation of a third strand by base-triples. This readily applicable approach provides unique insight into some of the interactions that stabilize RNA tertiary structure and enable function.

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Conformational Ensembles of Non-Coding Elements in the SARS-CoV-2 Genome from Molecular Dynamics Simulations

Cited by 3 publications

References 82 publications

Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex

Extended ensemble simulations of a SARS-CoV-2 nsp1–5’-UTR complex

Modeling the SARS-CoV-2 nsp1–5’-UTR complex via extended ensemble simulations

RNA triplex structures revealed by WAXS-driven MD simulations

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