Molecular dynamics simulations of antibiotic ceftaroline at the allosteric site of penicillin‐binding protein 2a (PBP2a)
Molecular dynamics simulations of antibiotic ceftaroline at the allosteric site of penicillin‐binding protein 2a (PBP2a)
Methicillin‐resistant Staphylococcus aureus (MRSA) tolerates β‐lactam antibiotics by carrying out cell wall synthesis with the transpeptidase Penicillin‐binding protein 2a (PBP2a), which cannot be inhibited by β‐lactams. It has been proposed that PBP2a's active site is protected by two loops to reduce the probability of it binding with β‐lactams. Previous crystallographic studies suggested that this protected active site opens for reaction once a native substrate binds at an allosteric domain of PBP2a. This opening was proposed for the new β‐lactam ceftaroline's mechanism in successfully treating MRSA infections, i. e. by it binding to the allosteric site, thereby opening the active site to inhibition. In this work, we investigate the binding of ceftaroline at this proposed allosteric site using molecular dynamics simulations. Unstable binding was observed using the major force fields CHARMM36 and Amber ff14SB, and free energy calculations were unable to confirm a strong allosteric effect. Our study suggests that the allosteric effect induced by ceftaroline is weak at best.
PBP2a, allosteric mechanism, molecular dynamics simulations, β-lactams
754-763
Chiang, Ying-Chih
94214b5c-7d58-44ba-86fe-27eba917159d
Wong, Mabel, Tung Yuet
97923566-eaa6-41af-b1af-83bb57d61753
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
1 July 2020
Chiang, Ying-Chih
94214b5c-7d58-44ba-86fe-27eba917159d
Wong, Mabel, Tung Yuet
97923566-eaa6-41af-b1af-83bb57d61753
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Chiang, Ying-Chih, Wong, Mabel, Tung Yuet and Essex, Jonathan W.
(2020)
Molecular dynamics simulations of antibiotic ceftaroline at the allosteric site of penicillin‐binding protein 2a (PBP2a).
Israel Journal of Chemistry, 60 (7), .
(doi:10.1002/ijch.202000012).
Abstract
Methicillin‐resistant Staphylococcus aureus (MRSA) tolerates β‐lactam antibiotics by carrying out cell wall synthesis with the transpeptidase Penicillin‐binding protein 2a (PBP2a), which cannot be inhibited by β‐lactams. It has been proposed that PBP2a's active site is protected by two loops to reduce the probability of it binding with β‐lactams. Previous crystallographic studies suggested that this protected active site opens for reaction once a native substrate binds at an allosteric domain of PBP2a. This opening was proposed for the new β‐lactam ceftaroline's mechanism in successfully treating MRSA infections, i. e. by it binding to the allosteric site, thereby opening the active site to inhibition. In this work, we investigate the binding of ceftaroline at this proposed allosteric site using molecular dynamics simulations. Unstable binding was observed using the major force fields CHARMM36 and Amber ff14SB, and free energy calculations were unable to confirm a strong allosteric effect. Our study suggests that the allosteric effect induced by ceftaroline is weak at best.
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ijch.202000012
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More information
e-pub ahead of print date: 16 April 2020
Published date: 1 July 2020
Additional Information:
Funding Information:
YCC thanks Prof. Peter Roach and Prof. Gergely Katona for sharing their views on electron densities of the ligands, Yui Tik Pang for sharing his protocol on optimising ligand force fields with FFTK, The Royal Society for funding (NF171278), and iSolutions at the University of Southampton for computing time on the Iridis5 cluster. MTYW thanks the BBSRC (BB/P504713/1) and UCB for funding.
Publisher Copyright:
© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
Keywords:
PBP2a, allosteric mechanism, molecular dynamics simulations, β-lactams
Identifiers
Local EPrints ID: 440705
URI: http://eprints.soton.ac.uk/id/eprint/440705
ISSN: 0021-2148
PURE UUID: ec8763bf-c430-4a34-97ca-78dd6ba1687b
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Date deposited: 13 May 2020 17:06
Last modified: 17 Mar 2024 02:40
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Author:
Ying-Chih Chiang
Author:
Mabel, Tung Yuet Wong
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