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Details of hydrophobic entanglement between small molecules and Braun’s lipoprotein within the cavity of the bacterial chaperone LolA

Details of hydrophobic entanglement between small molecules and Braun’s lipoprotein within the cavity of the bacterial chaperone LolA
Details of hydrophobic entanglement between small molecules and Braun’s lipoprotein within the cavity of the bacterial chaperone LolA
The cell envelope of Gram-negative bacteria is synthesized and maintained via mechanisms that are targets for development of novel antibiotics. Here we focus on the process of moving Braun’s lipoprotein (BLP) from the periplasmic space to the outer membrane of E. coli, via the LolA protein. In contrast to current thinking, we show that binding of multiple inhibitor molecules inside the hydrophobic cavity of LolA does not prevent subsequent binding of BLP inside the same cavity. Rather, based on our atomistic simulations we propose the theory that once inhibitors and BLP are bound inside the cavity of LolA, driven by hydrophobic interactions, they become entangled with each other. Our umbrella sampling calculations show that on the basis of energetics, it is more difficult to dislodge BLP from the cavity of LolA when it is uncomplexed compared to complexed with inhibitor. Thus the inhibitor reduces the affinity of BLP for the LolA cavity.
0028-0836
Boags, Alister
ec8b83d9-0601-4c97-8acc-3a26349a3076
Samsudin, Firdaus
b01e87a0-af50-44d6-bca4-f511c40165f9
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Boags, Alister
ec8b83d9-0601-4c97-8acc-3a26349a3076
Samsudin, Firdaus
b01e87a0-af50-44d6-bca4-f511c40165f9
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394

Boags, Alister, Samsudin, Firdaus and Khalid, Syma (2019) Details of hydrophobic entanglement between small molecules and Braun’s lipoprotein within the cavity of the bacterial chaperone LolA. Nature. (doi:10.1038/s41598-019-40170-z).

Record type: Article

Abstract

The cell envelope of Gram-negative bacteria is synthesized and maintained via mechanisms that are targets for development of novel antibiotics. Here we focus on the process of moving Braun’s lipoprotein (BLP) from the periplasmic space to the outer membrane of E. coli, via the LolA protein. In contrast to current thinking, we show that binding of multiple inhibitor molecules inside the hydrophobic cavity of LolA does not prevent subsequent binding of BLP inside the same cavity. Rather, based on our atomistic simulations we propose the theory that once inhibitors and BLP are bound inside the cavity of LolA, driven by hydrophobic interactions, they become entangled with each other. Our umbrella sampling calculations show that on the basis of energetics, it is more difficult to dislodge BLP from the cavity of LolA when it is uncomplexed compared to complexed with inhibitor. Thus the inhibitor reduces the affinity of BLP for the LolA cavity.

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Accepted/In Press date: 1 February 2019
e-pub ahead of print date: 6 March 2019

Identifiers

Local EPrints ID: 429091
URI: https://eprints.soton.ac.uk/id/eprint/429091
ISSN: 0028-0836
PURE UUID: ffd8eb3e-a702-4d4e-94e9-aa4cb32d0c36
ORCID for Firdaus Samsudin: ORCID iD orcid.org/0000-0003-2766-4459
ORCID for Syma Khalid: ORCID iD orcid.org/0000-0002-3694-5044

Catalogue record

Date deposited: 20 Mar 2019 17:30
Last modified: 20 Jul 2019 04:02

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