Uncovering cryptic pockets in the SARS-CoV-2 spike glycoprotein
Uncovering cryptic pockets in the SARS-CoV-2 spike glycoprotein
The COVID-19 pandemic has prompted a rapid response in vaccine and drug development. Herein, we modeled a complete membrane-embedded SARS-CoV-2 spike glycoprotein and used molecular dynamics simulations with benzene probes designed to enhance discovery of cryptic pockets. This approach recapitulated lipid and host metabolite binding sites previously characterized by cryo-electron microscopy, revealing likely ligand entry routes, and uncovered a novel cryptic pocket with promising druggable properties located underneath the 617-628 loop. A full representation of glycan moieties was essential to accurately describe pocket dynamics. A multi-conformational behavior of the 617-628 loop in simulations was validated using hydrogen-deuterium exchange mass spectrometry experiments, supportive of opening and closing dynamics. The pocket is the site of multiple mutations associated with increased transmissibility found in SARS-CoV-2 variants of concern including Omicron. Collectively, this work highlights the utility of the benzene mapping approach in uncovering potential druggable sites on the surface of SARS-CoV-2 targets.
COVID-19, benzene mapping, coronavirus, cryptic pockets, glycans, hydrogen-deuterium exchange mass spectrometry, molecular dynamics simulation, omicron, spike protein
1062-1074.e4
Zuzic, Lorena
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Samsudin, Firdaus
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Shivgan, Aishwary T.
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Raghuvamsi, Palur V.
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Marzinek, Jan K.
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Boags, Alister
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Pedebos, Conrado
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Tulsian, Nikhil K.
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Warwicker, Jim
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MacAry, Paul
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Crispin, Max
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Khalid, Syma
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Anand, Ganesh S.
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Bond, Peter J.
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4 August 2022
Zuzic, Lorena
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Samsudin, Firdaus
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Shivgan, Aishwary T.
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Raghuvamsi, Palur V.
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Marzinek, Jan K.
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Boags, Alister
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Pedebos, Conrado
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Tulsian, Nikhil K.
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Warwicker, Jim
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MacAry, Paul
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Crispin, Max
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Khalid, Syma
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Anand, Ganesh S.
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Bond, Peter J.
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Zuzic, Lorena, Samsudin, Firdaus, Shivgan, Aishwary T., Raghuvamsi, Palur V., Marzinek, Jan K., Boags, Alister, Pedebos, Conrado, Tulsian, Nikhil K., Warwicker, Jim, MacAry, Paul, Crispin, Max, Khalid, Syma, Anand, Ganesh S. and Bond, Peter J.
(2022)
Uncovering cryptic pockets in the SARS-CoV-2 spike glycoprotein.
Structure, 30 (8), .
(doi:10.1016/j.str.2022.05.006).
Abstract
The COVID-19 pandemic has prompted a rapid response in vaccine and drug development. Herein, we modeled a complete membrane-embedded SARS-CoV-2 spike glycoprotein and used molecular dynamics simulations with benzene probes designed to enhance discovery of cryptic pockets. This approach recapitulated lipid and host metabolite binding sites previously characterized by cryo-electron microscopy, revealing likely ligand entry routes, and uncovered a novel cryptic pocket with promising druggable properties located underneath the 617-628 loop. A full representation of glycan moieties was essential to accurately describe pocket dynamics. A multi-conformational behavior of the 617-628 loop in simulations was validated using hydrogen-deuterium exchange mass spectrometry experiments, supportive of opening and closing dynamics. The pocket is the site of multiple mutations associated with increased transmissibility found in SARS-CoV-2 variants of concern including Omicron. Collectively, this work highlights the utility of the benzene mapping approach in uncovering potential druggable sites on the surface of SARS-CoV-2 targets.
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More information
Accepted/In Press date: 10 May 2022
e-pub ahead of print date: 3 June 2022
Published date: 4 August 2022
Additional Information:
Funding Information: this work was supported by BII of A∗STAR. P.J.B. J.K.M. and F.S. acknowledge funding from grant FY21_CF_HTPO SEED_ID_BII_C211418001 funded by A∗STAR. L.Z. thanks the A∗STAR Graduate Academy (A∗GA) for funding. Simulations were performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg), the A∗STAR Computational Resource Centre (A∗CRC), Iridis 5 supercomputer at the University of Southampton, ARCHER provided by the UK HECBioSim, and the supercomputer Fugaku provided by RIKEN through the HPCI System Research Project (Project ID: hp200303). G.S.A. acknowledges startup funds from The Pennsylvania State University. Conceptualization, L.Z. F.S. P.J.B.; Methodology, L.Z. F.S. A.T.S. P.V.R.; Investigation, L.Z. F.S. A.T.S. P.V.R. J.K.M. A.B. C.P. N.K.T.; Formal Analysis, L.Z. F.S. P.V.R.; Visualization, L.Z. F.S. P.V.R; Writing – Original Draft, L.Z. F.S. P.V.R. P.J.B; Writing – Review & Editing, L.Z. F.S. P.V.R. J.W. P.M. M.C. S.K. G.S.A, P.J.B; Supervision, J.W. P.M. M.C. S.K. G.S.A, P.J.B; Project Administration, J.W. P.M. M.C. S.K. G.S.A, P.J.B.; Funding Acquisition, J.W. P.M. M.C. S.K. G.S.A, P.J.B. The authors declare no competing interests.
Funding Information: this work was supported by BII of A ∗ STAR . P.J.B., J.K.M., and F.S. acknowledge funding from grant FY21_CF_HTPO SEED_ID_BII_C211418001 funded by A ∗ STAR . L.Z. thanks the A ∗ STAR Graduate Academy ( A∗GA ) for funding. Simulations were performed on resources of the National Supercomputing Centre, Singapore ( https://www.nscc.sg ), the A ∗ STAR Computational Resource Centre (A ∗ CRC), Iridis 5 supercomputer at the University of Southampton, ARCHER provided by the UK HECBioSim, and the supercomputer Fugaku provided by RIKEN through the HPCI System Research Project (Project ID: hp200303). G.S.A. acknowledges startup funds from The Pennsylvania State University .
Keywords:
COVID-19, benzene mapping, coronavirus, cryptic pockets, glycans, hydrogen-deuterium exchange mass spectrometry, molecular dynamics simulation, omicron, spike protein
Identifiers
Local EPrints ID: 469647
URI: http://eprints.soton.ac.uk/id/eprint/469647
ISSN: 0969-2126
PURE UUID: 79eaff8c-ff73-4411-9681-7262fe571c56
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Date deposited: 21 Sep 2022 16:59
Last modified: 17 Mar 2024 07:28
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Contributors
Author:
Lorena Zuzic
Author:
Firdaus Samsudin
Author:
Aishwary T. Shivgan
Author:
Palur V. Raghuvamsi
Author:
Jan K. Marzinek
Author:
Alister Boags
Author:
Conrado Pedebos
Author:
Nikhil K. Tulsian
Author:
Jim Warwicker
Author:
Paul MacAry
Author:
Syma Khalid
Author:
Ganesh S. Anand
Author:
Peter J. Bond
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