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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)
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.
molecular dynamics simulations, β-lactams, allosteric mechanism, PBP2a
0021-2148
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
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. (doi:10.1002/ijch.202000012).

Record type: Article

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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e-pub ahead of print date: 16 April 2020
Keywords: molecular dynamics simulations, β-lactams, allosteric mechanism, PBP2a

Identifiers

Local EPrints ID: 440705
URI: http://eprints.soton.ac.uk/id/eprint/440705
ISSN: 0021-2148
PURE UUID: ec8763bf-c430-4a34-97ca-78dd6ba1687b
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

Catalogue record

Date deposited: 13 May 2020 17:06
Last modified: 23 May 2020 00:25

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