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Interaction of the antimicrobial peptide polymyxin B1 with both membranes of E. coli: a molecular dynamics study.

Berglund NA, Piggot TJ, Jefferies D, Sessions RB, Bond PJ, Khalid S - PLoS Comput. Biol. (2015)

Bottom Line: The results of >16 microseconds of simulation predict that polymyxin B1 is likely to interact with the membranes via distinct mechanisms.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.

View Article: PubMed Central - PubMed

Affiliation: School of Chemistry, University of Southampton, Highfield, Southampton, United Kingdom; Bioinformatics Institute (A*STAR), Singapore.

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 microseconds 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.

No MeSH data available.


Related in: MedlinePlus

Summary of interactions with the lipid A bilayer.A- Snapshot showing one PMB1 peptide inserting into the lipid A bilayer, taken from time = 3 microseconds. (PMB1 (A) non-tail regions: cyan, licorice format, PMB1 tails: cyan, VdW format, PMB1 (B): non-tail regions: dark blue, licorice, PMB1 tails: dark blue, VdW format, lipid phosphate groups: orange, VdW format, lipid A: yellow, lines format). B- DAB residues of PMB1 parting the lipid A headgroups, colored as above with DAB in lime, VdW format.
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pcbi.1004180.g002: Summary of interactions with the lipid A bilayer.A- Snapshot showing one PMB1 peptide inserting into the lipid A bilayer, taken from time = 3 microseconds. (PMB1 (A) non-tail regions: cyan, licorice format, PMB1 tails: cyan, VdW format, PMB1 (B): non-tail regions: dark blue, licorice, PMB1 tails: dark blue, VdW format, lipid phosphate groups: orange, VdW format, lipid A: yellow, lines format). B- DAB residues of PMB1 parting the lipid A headgroups, colored as above with DAB in lime, VdW format.

Mentions: Aggregation of PMB1 peptides was observed at the membrane surface. Interaction of the DAB residues with the membrane surface during aggregation caused water molecules to move towards the membrane. We measured an increase in solvent penetration within 1.6 nm of the membrane centre (S4 Fig), although not to the same extent as the change observed in the asymmetric OM. The major difference between this model and the asymmetric bilayer is that we observed spontaneous insertion of the fatty acid tail of one PMB1 molecule into the lipid A bilayer, ~1 microsecond after peptide aggregation. Interestingly, DAB residues of this and nearby PMB1 peptides were observed to interact with the negatively charged phosphate groups on the membrane surface, causing phosphate groups of adjacent lipids to move apart to facilitate fatty acid tail insertion into the membrane core (Fig 2).


Interaction of the antimicrobial peptide polymyxin B1 with both membranes of E. coli: a molecular dynamics study.

Berglund NA, Piggot TJ, Jefferies D, Sessions RB, Bond PJ, Khalid S - PLoS Comput. Biol. (2015)

Summary of interactions with the lipid A bilayer.A- Snapshot showing one PMB1 peptide inserting into the lipid A bilayer, taken from time = 3 microseconds. (PMB1 (A) non-tail regions: cyan, licorice format, PMB1 tails: cyan, VdW format, PMB1 (B): non-tail regions: dark blue, licorice, PMB1 tails: dark blue, VdW format, lipid phosphate groups: orange, VdW format, lipid A: yellow, lines format). B- DAB residues of PMB1 parting the lipid A headgroups, colored as above with DAB in lime, VdW format.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401565&req=5

pcbi.1004180.g002: Summary of interactions with the lipid A bilayer.A- Snapshot showing one PMB1 peptide inserting into the lipid A bilayer, taken from time = 3 microseconds. (PMB1 (A) non-tail regions: cyan, licorice format, PMB1 tails: cyan, VdW format, PMB1 (B): non-tail regions: dark blue, licorice, PMB1 tails: dark blue, VdW format, lipid phosphate groups: orange, VdW format, lipid A: yellow, lines format). B- DAB residues of PMB1 parting the lipid A headgroups, colored as above with DAB in lime, VdW format.
Mentions: Aggregation of PMB1 peptides was observed at the membrane surface. Interaction of the DAB residues with the membrane surface during aggregation caused water molecules to move towards the membrane. We measured an increase in solvent penetration within 1.6 nm of the membrane centre (S4 Fig), although not to the same extent as the change observed in the asymmetric OM. The major difference between this model and the asymmetric bilayer is that we observed spontaneous insertion of the fatty acid tail of one PMB1 molecule into the lipid A bilayer, ~1 microsecond after peptide aggregation. Interestingly, DAB residues of this and nearby PMB1 peptides were observed to interact with the negatively charged phosphate groups on the membrane surface, causing phosphate groups of adjacent lipids to move apart to facilitate fatty acid tail insertion into the membrane core (Fig 2).

Bottom Line: The results of >16 microseconds of simulation predict that polymyxin B1 is likely to interact with the membranes via distinct mechanisms.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.

View Article: PubMed Central - PubMed

Affiliation: School of Chemistry, University of Southampton, Highfield, Southampton, United Kingdom; Bioinformatics Institute (A*STAR), Singapore.

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 microseconds 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.

No MeSH data available.


Related in: MedlinePlus