Modelling the Active SARS-CoV-2 Helicase Complex as a Basis for Structurebased Inhibitor Design

Dénes Berta; Magd Badaoui; Sam Alexander Martino; Pedro J. Buigues; Andrei V. Pisliakov; Nadia Elghobashi-Meinhardt; Geoff Wells; Sarah A. Harris; Elisa Frezza; Edina Rosta

doi:10.1039/D1SC02775A

Modelling the Active SARS-CoV-2 Helicase Complex as a Basis for Structurebased Inhibitor Design

Dénes Berta, Magd Badaoui, Sam Alexander Martino, Pedro J. Buigues, Andrei V. Pisliakov, Nadia Elghobashi-Meinhardt, Geoff Wells, Sarah A. Harris, Elisa Frezza, Edina Rosta

Physics

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

84 Downloads (Pure)

Abstract

The RNA helicase (non-structural protein 13, NSP13) of SARS-CoV-2 is essential for viral replication, and it is highly conserved among the coronaviridae family, thus a prominent drug target to treat COVID-19. We present here structural models and dynamics of the helicase in complex with its native substrates based on thorough analysis of homologous sequences and existing experimental structures. We performed and analysed microseconds of molecular dynamics (MD) simulations, and our model provides valuable insights to the binding of the ATP and ssRNA at the atomic level. We identify the principal motions characterising the enzyme and highlight the effect of the natural substrates on this dynamics. Furthermore, allosteric binding sites are suggested by our pocket analysis. Our obtained structural and dynamical insights are important for subsequent studies of the catalytic function and for the development of specific inhibitors at our characterised binding pockets for this promising COVID-19 drug target.

Original language	English
Pages (from-to)	13492-13505
Number of pages	14
Journal	Chemical Science
Volume	12
Issue number	40
Early online date	6 Sept 2021
DOIs	https://doi.org/10.1039/D1SC02775A
Publication status	Published - 28 Oct 2021

ASJC Scopus subject areas

General Chemistry

Access to Document

10.1039/D1SC02775ALicence: CC BY

Final published version
All publication charges for this article have been paid for by the Royal Society of Chemistry
Final published version, 2.32 MBLicence: CC BY

Cite this

@article{baefeed58df5474b85f57afbc30a1e9d,

title = "Modelling the Active SARS-CoV-2 Helicase Complex as a Basis for Structurebased Inhibitor Design",

abstract = "The RNA helicase (non-structural protein 13, NSP13) of SARS-CoV-2 is essential for viral replication, and it is highly conserved among the coronaviridae family, thus a prominent drug target to treat COVID-19. We present here structural models and dynamics of the helicase in complex with its native substrates based on thorough analysis of homologous sequences and existing experimental structures. We performed and analysed microseconds of molecular dynamics (MD) simulations, and our model provides valuable insights to the binding of the ATP and ssRNA at the atomic level. We identify the principal motions characterising the enzyme and highlight the effect of the natural substrates on this dynamics. Furthermore, allosteric binding sites are suggested by our pocket analysis. Our obtained structural and dynamical insights are important for subsequent studies of the catalytic function and for the development of specific inhibitors at our characterised binding pockets for this promising COVID-19 drug target.",

author = "D{\'e}nes Berta and Magd Badaoui and Martino, {Sam Alexander} and Buigues, {Pedro J.} and Pisliakov, {Andrei V.} and Nadia Elghobashi-Meinhardt and Geoff Wells and Harris, {Sarah A.} and Elisa Frezza and Edina Rosta",

note = "ER, DB, MB, and SAM acknowledge funding from ERC Starting Grant (project 757850 BioNet). This project made use of time on ARCHER granted via the UK High-End Computing Consortium for Biomolecular Simulation, HECBioSim (http://hecbiosim.ac.uk), supported by EPSRC (grant no. EP/R013012/1). We would like to thank GENCI for a generous allocation of computing time at CINES within the action “Project contre le COVID 19” and the project DARI A0080711431. We are also grateful for resourced provided by the Leeds ARC HPC service.",

year = "2021",

month = oct,

day = "28",

doi = "10.1039/D1SC02775A",

language = "English",

volume = "12",

pages = "13492--13505",

journal = "Chemical Science",

issn = "2041-6520",

publisher = "Royal Society of Chemistry",

number = "40",

}

TY - JOUR

T1 - Modelling the Active SARS-CoV-2 Helicase Complex as a Basis for Structurebased Inhibitor Design

AU - Berta, Dénes

AU - Badaoui, Magd

AU - Martino, Sam Alexander

AU - Buigues, Pedro J.

AU - Pisliakov, Andrei V.

AU - Elghobashi-Meinhardt, Nadia

AU - Wells, Geoff

AU - Harris, Sarah A.

AU - Frezza, Elisa

AU - Rosta, Edina

N1 - ER, DB, MB, and SAM acknowledge funding from ERC Starting Grant (project 757850 BioNet). This project made use of time on ARCHER granted via the UK High-End Computing Consortium for Biomolecular Simulation, HECBioSim (http://hecbiosim.ac.uk), supported by EPSRC (grant no. EP/R013012/1). We would like to thank GENCI for a generous allocation of computing time at CINES within the action “Project contre le COVID 19” and the project DARI A0080711431. We are also grateful for resourced provided by the Leeds ARC HPC service.

PY - 2021/10/28

Y1 - 2021/10/28

N2 - The RNA helicase (non-structural protein 13, NSP13) of SARS-CoV-2 is essential for viral replication, and it is highly conserved among the coronaviridae family, thus a prominent drug target to treat COVID-19. We present here structural models and dynamics of the helicase in complex with its native substrates based on thorough analysis of homologous sequences and existing experimental structures. We performed and analysed microseconds of molecular dynamics (MD) simulations, and our model provides valuable insights to the binding of the ATP and ssRNA at the atomic level. We identify the principal motions characterising the enzyme and highlight the effect of the natural substrates on this dynamics. Furthermore, allosteric binding sites are suggested by our pocket analysis. Our obtained structural and dynamical insights are important for subsequent studies of the catalytic function and for the development of specific inhibitors at our characterised binding pockets for this promising COVID-19 drug target.

AB - The RNA helicase (non-structural protein 13, NSP13) of SARS-CoV-2 is essential for viral replication, and it is highly conserved among the coronaviridae family, thus a prominent drug target to treat COVID-19. We present here structural models and dynamics of the helicase in complex with its native substrates based on thorough analysis of homologous sequences and existing experimental structures. We performed and analysed microseconds of molecular dynamics (MD) simulations, and our model provides valuable insights to the binding of the ATP and ssRNA at the atomic level. We identify the principal motions characterising the enzyme and highlight the effect of the natural substrates on this dynamics. Furthermore, allosteric binding sites are suggested by our pocket analysis. Our obtained structural and dynamical insights are important for subsequent studies of the catalytic function and for the development of specific inhibitors at our characterised binding pockets for this promising COVID-19 drug target.

UR - http://www.scopus.com/inward/record.url?scp=85117790707&partnerID=8YFLogxK

U2 - 10.1039/D1SC02775A

DO - 10.1039/D1SC02775A

M3 - Article

SN - 2041-6520

VL - 12

SP - 13492

EP - 13505

JO - Chemical Science

JF - Chemical Science

IS - 40

ER -

Modelling the Active SARS-CoV-2 Helicase Complex as a Basis for Structurebased Inhibitor Design

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Modelling the active SARS-CoV-2 helicase complex as a basis for structure-based inhibitor design

Cite this