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Interaction of the antimicrobial peptide polymyxin b1 with both membranes of E. coli: a molecular dynamics study

Interaction of the antimicrobial peptide polymyxin b1 with both membranes of E. coli: a molecular dynamics study
Interaction of the antimicrobial peptide polymyxin b1 with both membranes of E. coli: a molecular dynamics study
Antimicrobial peptides are small, cationic proteins that can induce lysis of bacterial cells through interaction with their membranes. Different mechanisms for cell lysis have been proposed, but these models tend to neglect the role of the chemical composition of the membrane, which differs between bacterial species and can be heterogeneous even within a single cell. Moreover, the cell envelope of Gram-negative bacteria such as E. coli contains two membranes with differing compositions. To this end, we report the first molecular dynamics simulation study of the interaction of the antimicrobial peptide, polymyxin B1 with complex models of both the inner and outer membranes of E. coli. The results of > 16 micro-seconds of simulation predict that polymyxin B1 is likely to interact with the membranes via distinct mechanisms. The lipopeptides aggregate in the lipopolysaccharide headgroup region of the outer membrane with limited tendency for insertion within the lipid A tails. In contrast, the lipopeptides readily insert into the inner membrane core, and the concomitant increased hydration may be responsible for bilayer destabilization and antimicrobial function. Given the urgent need to develop novel, potent antibiotics, the results presented here reveal key mechanistic details that may be exploited for future rational drug development.
1553-734X
1-17
Berglund, Nils
01f23146-6b2d-4c6f-a090-85e6dad99ec3
Piggot, Thomas J.
75829b71-d73b-43d1-b24f-3e70c2c4d0c8
Jefferies, Damien
8df97e21-8df6-4571-bfbe-3edc41e16967
Sessions, Richard B.
d0b37bc6-44a8-4ac9-806c-666885865af1
Bond, Peter J.
08f46940-85e8-44c4-a368-d94342a10fd6
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Berglund, Nils
01f23146-6b2d-4c6f-a090-85e6dad99ec3
Piggot, Thomas J.
75829b71-d73b-43d1-b24f-3e70c2c4d0c8
Jefferies, Damien
8df97e21-8df6-4571-bfbe-3edc41e16967
Sessions, Richard B.
d0b37bc6-44a8-4ac9-806c-666885865af1
Bond, Peter J.
08f46940-85e8-44c4-a368-d94342a10fd6
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394

Berglund, Nils, Piggot, Thomas J., Jefferies, Damien, Sessions, Richard B., Bond, Peter J. and Khalid, Syma (2015) Interaction of the antimicrobial peptide polymyxin b1 with both membranes of E. coli: a molecular dynamics study. PLoS computational biology, 11 (4), 1-17. (doi:10.1371/journal.pcbi.1004180). (PMID:25885324)

Record type: Article

Abstract

Antimicrobial peptides are small, cationic proteins that can induce lysis of bacterial cells through interaction with their membranes. Different mechanisms for cell lysis have been proposed, but these models tend to neglect the role of the chemical composition of the membrane, which differs between bacterial species and can be heterogeneous even within a single cell. Moreover, the cell envelope of Gram-negative bacteria such as E. coli contains two membranes with differing compositions. To this end, we report the first molecular dynamics simulation study of the interaction of the antimicrobial peptide, polymyxin B1 with complex models of both the inner and outer membranes of E. coli. The results of > 16 micro-seconds of simulation predict that polymyxin B1 is likely to interact with the membranes via distinct mechanisms. The lipopeptides aggregate in the lipopolysaccharide headgroup region of the outer membrane with limited tendency for insertion within the lipid A tails. In contrast, the lipopeptides readily insert into the inner membrane core, and the concomitant increased hydration may be responsible for bilayer destabilization and antimicrobial function. Given the urgent need to develop novel, potent antibiotics, the results presented here reveal key mechanistic details that may be exploited for future rational drug development.

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Accepted/In Press date: 6 February 2015
Published date: 17 April 2015
Organisations: Computational Systems Chemistry

Identifiers

Local EPrints ID: 395511
URI: http://eprints.soton.ac.uk/id/eprint/395511
ISSN: 1553-734X
PURE UUID: 7fef138d-8ea0-4c40-8a08-3c4929e7f010
ORCID for Syma Khalid: ORCID iD orcid.org/0000-0002-3694-5044

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Date deposited: 31 May 2016 14:34
Last modified: 05 Nov 2019 01:45

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Contributors

Author: Nils Berglund
Author: Thomas J. Piggot
Author: Damien Jefferies
Author: Richard B. Sessions
Author: Peter J. Bond
Author: Syma Khalid ORCID iD

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