Conformational dynamics and putative substrate extrusion pathways of the N-glycosylated outer membrane factor CmeC from Campylobacter jejuni
Conformational dynamics and putative substrate extrusion pathways of the N-glycosylated outer membrane factor CmeC from Campylobacter jejuni
The outer membrane factor CmeC of the efflux machinery CmeABC plays an important role in conferring antibiotic and bile resistance to Campylobacter jejuni. Curiously, the protein is N-glycosylated, with the glycans playing a key role in the effective function of this system. In this work we have employed atomistic equilibrium molecular dynamics simulations of CmeC in a representative model of the C. jejuni outer membrane to characterise the dynamics of the protein and its associated glycans. We show that the glycans are more conformationally labile than had previously been thought. The extracellular loops of CmeC visit the open and closed states freely suggesting the absence of a gating mechanism on this side, while the narrow periplasmic entrance remains tightly closed, regulated via coordination to solvated cations. We identify several cation binding sites on the interior surface of the protein. Additionally, we used steered molecular dynamics simulations to elucidate translocation pathways for a bile acid and a macrolide antibiotic. These, and additional equilibrium simulations suggest that the anionic bile acid utilises multivalent cations to climb the ladder of acidic residues that line the interior surface of the protein.
Newman, Kahlan E.
7fccd66d-2aa1-4dd6-b477-2ad528389f83
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
January 2023
Newman, Kahlan E.
7fccd66d-2aa1-4dd6-b477-2ad528389f83
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Newman, Kahlan E. and Khalid, Syma
(2023)
Conformational dynamics and putative substrate extrusion pathways of the N-glycosylated outer membrane factor CmeC from Campylobacter jejuni.
PLoS Computational Biology, 19 (1), [e1010841].
(doi:10.1371/journal.pcbi.1010841).
Abstract
The outer membrane factor CmeC of the efflux machinery CmeABC plays an important role in conferring antibiotic and bile resistance to Campylobacter jejuni. Curiously, the protein is N-glycosylated, with the glycans playing a key role in the effective function of this system. In this work we have employed atomistic equilibrium molecular dynamics simulations of CmeC in a representative model of the C. jejuni outer membrane to characterise the dynamics of the protein and its associated glycans. We show that the glycans are more conformationally labile than had previously been thought. The extracellular loops of CmeC visit the open and closed states freely suggesting the absence of a gating mechanism on this side, while the narrow periplasmic entrance remains tightly closed, regulated via coordination to solvated cations. We identify several cation binding sites on the interior surface of the protein. Additionally, we used steered molecular dynamics simulations to elucidate translocation pathways for a bile acid and a macrolide antibiotic. These, and additional equilibrium simulations suggest that the anionic bile acid utilises multivalent cations to climb the ladder of acidic residues that line the interior surface of the protein.
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journal.pcbi.1010841
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Accepted/In Press date: 22 December 2022
e-pub ahead of print date: 13 January 2023
Published date: January 2023
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© 2023 Newman, Khalid. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The authors acknowledge access to the following High Performance Computing resources: Iridis 5 at the University of Southampton and the ARCHER2 UK National Computing Service to which access was granted via HECBioSim, the UK High-End Computing Consortium for Biomolecular Simulation (EPSRC grant no. EP/R029407/1).
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Local EPrints ID: 475919
URI: http://eprints.soton.ac.uk/id/eprint/475919
ISSN: 1553-734X
PURE UUID: 2af56beb-cb66-490a-9452-f645c208d9d2
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Date deposited: 31 Mar 2023 16:31
Last modified: 17 Mar 2024 03:11
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Author:
Kahlan E. Newman
Author:
Syma Khalid
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