Dynamical Nonequilibrium Molecular Dynamics Simulations Identify Allosteric Sites and Positions Associated with Drug Resistance in the SARS-CoV-2 Main Protease

H. T. Henry Chan; A. Sofia F. Oliveira; Christopher J. Schofield; Adrian J. Mulholland; Fernanda Duarte

doi:10.1021/jacsau.3c00185

Dynamical Nonequilibrium Molecular Dynamics Simulations Identify Allosteric Sites and Positions Associated with Drug Resistance in the SARS-CoV-2 Main Protease

H. T. Henry Chan, A. Sofia F. Oliveira, Christopher J. Schofield, Adrian J. Mulholland^*, Fernanda Duarte^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

18 Citations (Scopus)

Abstract

The SARS-CoV-2 main protease (Mpro) plays an essential role in the coronavirus lifecycle by catalyzing hydrolysis of the viral polyproteins at specific sites. Mpro is the target of drugs, such as nirmatrelvir, though resistant mutants have emerged that threaten drug efficacy. Despite its importance, questions remain on the mechanism of how Mpro binds its substrates. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to evaluate structural and dynamical responses of Mpro to the presence and absence of a substrate. The results highlight communication between the Mpro dimer subunits and identify networks, including some far from the active site, that link the active site with a known allosteric inhibition site, or which are associated with nirmatrelvir resistance. They imply that some mutations enable resistance by altering the allosteric behavior of Mpro. More generally, the results show the utility of the D-NEMD technique for identifying functionally relevant allosteric sites and networks including those relevant to resistance.

Original language	English
Pages (from-to)	1767-1774
Number of pages	8
Journal	JACS Au
Volume	3
Issue number	6
Early online date	7 Jun 2023
DOIs	https://doi.org/10.1021/jacsau.3c00185
Publication status	Published - 26 Jun 2023

Bibliographical note

Funding Information:
H.T.H.C. thanks the Clarendon Fund, New College Oxford, and the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for a studentship, generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex. A.J.M. and A.S.F.O. thank EPSRC (grant number EP/M022609/1), BBSRC (grant number BB/R016445/1), and ERC (Advanced Grant PREDACTED https://cordis.europa.eu/project/id/101021207 ) for support (funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme, grant agreement no. 101021207). This project made use of time on HPC granted via the UK High-End Computing Consortium for Biomolecular Simulation, HECBioSim ( http://hecbiosim.ac.uk ), supported by EPSRC (grant no. EP/R029407/1).

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society

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Physical & Theoretical

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10.1021/jacsau.3c00185Licence: CC BY

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Cite this

@article{04339df6128a4ff4b7b5bf826aefc48b,

title = "Dynamical Nonequilibrium Molecular Dynamics Simulations Identify Allosteric Sites and Positions Associated with Drug Resistance in the SARS-CoV-2 Main Protease",

abstract = "The SARS-CoV-2 main protease (Mpro) plays an essential role in the coronavirus lifecycle by catalyzing hydrolysis of the viral polyproteins at specific sites. Mpro is the target of drugs, such as nirmatrelvir, though resistant mutants have emerged that threaten drug efficacy. Despite its importance, questions remain on the mechanism of how Mpro binds its substrates. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to evaluate structural and dynamical responses of Mpro to the presence and absence of a substrate. The results highlight communication between the Mpro dimer subunits and identify networks, including some far from the active site, that link the active site with a known allosteric inhibition site, or which are associated with nirmatrelvir resistance. They imply that some mutations enable resistance by altering the allosteric behavior of Mpro. More generally, the results show the utility of the D-NEMD technique for identifying functionally relevant allosteric sites and networks including those relevant to resistance.",

author = "Chan, \{H. T. Henry\} and Oliveira, \{A. Sofia F.\} and Schofield, \{Christopher J.\} and Mulholland, \{Adrian J.\} and Fernanda Duarte",

note = "Funding Information: H.T.H.C. thanks the Clarendon Fund, New College Oxford, and the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for a studentship, generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex. A.J.M. and A.S.F.O. thank EPSRC (grant number EP/M022609/1), BBSRC (grant number BB/R016445/1), and ERC (Advanced Grant PREDACTED https://cordis.europa.eu/project/id/101021207 ) for support (funding from the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation programme, grant agreement no. 101021207). This project made use of time on HPC granted via the UK High-End Computing Consortium for Biomolecular Simulation, HECBioSim ( http://hecbiosim.ac.uk ), supported by EPSRC (grant no. EP/R029407/1). Publisher Copyright: {\textcopyright} 2023 The Authors. Published by American Chemical Society",

year = "2023",

month = jun,

day = "26",

doi = "10.1021/jacsau.3c00185",

language = "English",

volume = "3",

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Dynamical Nonequilibrium Molecular Dynamics Simulations Identify Allosteric Sites and Positions Associated with Drug Resistance in the SARS-CoV-2 Main Protease. / Chan, H. T. Henry; Oliveira, A. Sofia F.; Schofield, Christopher J. et al.
In: JACS Au, Vol. 3, No. 6, 26.06.2023, p. 1767-1774.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - Dynamical Nonequilibrium Molecular Dynamics Simulations Identify Allosteric Sites and Positions Associated with Drug Resistance in the SARS-CoV-2 Main Protease

AU - Chan, H. T. Henry

AU - Oliveira, A. Sofia F.

AU - Schofield, Christopher J.

AU - Mulholland, Adrian J.

AU - Duarte, Fernanda

N1 - Funding Information: H.T.H.C. thanks the Clarendon Fund, New College Oxford, and the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1) for a studentship, generously supported by AstraZeneca, Diamond Light Source, Defence Science and Technology Laboratory, Evotec, GlaxoSmithKline, Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB, and Vertex. A.J.M. and A.S.F.O. thank EPSRC (grant number EP/M022609/1), BBSRC (grant number BB/R016445/1), and ERC (Advanced Grant PREDACTED https://cordis.europa.eu/project/id/101021207 ) for support (funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme, grant agreement no. 101021207). This project made use of time on HPC granted via the UK High-End Computing Consortium for Biomolecular Simulation, HECBioSim ( http://hecbiosim.ac.uk ), supported by EPSRC (grant no. EP/R029407/1). Publisher Copyright: © 2023 The Authors. Published by American Chemical Society

PY - 2023/6/26

Y1 - 2023/6/26

N2 - The SARS-CoV-2 main protease (Mpro) plays an essential role in the coronavirus lifecycle by catalyzing hydrolysis of the viral polyproteins at specific sites. Mpro is the target of drugs, such as nirmatrelvir, though resistant mutants have emerged that threaten drug efficacy. Despite its importance, questions remain on the mechanism of how Mpro binds its substrates. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to evaluate structural and dynamical responses of Mpro to the presence and absence of a substrate. The results highlight communication between the Mpro dimer subunits and identify networks, including some far from the active site, that link the active site with a known allosteric inhibition site, or which are associated with nirmatrelvir resistance. They imply that some mutations enable resistance by altering the allosteric behavior of Mpro. More generally, the results show the utility of the D-NEMD technique for identifying functionally relevant allosteric sites and networks including those relevant to resistance.

AB - The SARS-CoV-2 main protease (Mpro) plays an essential role in the coronavirus lifecycle by catalyzing hydrolysis of the viral polyproteins at specific sites. Mpro is the target of drugs, such as nirmatrelvir, though resistant mutants have emerged that threaten drug efficacy. Despite its importance, questions remain on the mechanism of how Mpro binds its substrates. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to evaluate structural and dynamical responses of Mpro to the presence and absence of a substrate. The results highlight communication between the Mpro dimer subunits and identify networks, including some far from the active site, that link the active site with a known allosteric inhibition site, or which are associated with nirmatrelvir resistance. They imply that some mutations enable resistance by altering the allosteric behavior of Mpro. More generally, the results show the utility of the D-NEMD technique for identifying functionally relevant allosteric sites and networks including those relevant to resistance.

UR - https://doi.org/10.1021/jacsau.3c00185

U2 - 10.1021/jacsau.3c00185

DO - 10.1021/jacsau.3c00185

M3 - Article (Academic Journal)

C2 - 37384148

SN - 2691-3704

VL - 3

SP - 1767

EP - 1774

JO - JACS Au

JF - JACS Au

IS - 6

ER -

Dynamical Nonequilibrium Molecular Dynamics Simulations Identify Allosteric Sites and Positions Associated with Drug Resistance in the SARS-CoV-2 Main Protease

Abstract

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PREDACTED: Predictive simulation for Enzyme Dynamics, Antimicrobial resistance, Catalysis and Thermoadaptation for Evolution and Design

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Dynamical Nonequilibrium Molecular Dynamics Simulations Identify Allosteric Sites and Positions Associated with Drug Resistance in the SARS-CoV-2 Main Protease

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Bibliographical note

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PREDACTED: Predictive simulation for Enzyme Dynamics, Antimicrobial resistance, Catalysis and Thermoadaptation for Evolution and Design

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HPC (High Performance Computing) and HTC (High Throughput Computing) Facilities

Research Data Storage Facility (RDSF)

Cite this