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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 PMB1 interaction with the three membrane models.The peptides are shown at the start (A, C and E) and end of (B, D and F) simulations of the asymmetric OM, the lipid A bilayer and the symmetric IM models respectively. Insertion into the lipid A bilayer and the model inner membrane is clearly visible in the panels D and F corresponding to the end of these simulations respectively. The colour scheme is consistent with the previous figures.
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pcbi.1004180.g004: Summary of PMB1 interaction with the three membrane models.The peptides are shown at the start (A, C and E) and end of (B, D and F) simulations of the asymmetric OM, the lipid A bilayer and the symmetric IM models respectively. Insertion into the lipid A bilayer and the model inner membrane is clearly visible in the panels D and F corresponding to the end of these simulations respectively. The colour scheme is consistent with the previous figures.

Mentions: Within 100 ns of binding to the membrane surface, the fatty acid tails of all of the PMB1 peptides inserted into the hydrophobic core of the bilayer. We observed that the D-Phe residues of the peptides also became embedded within the acyl tail region of the membrane within this timeframe (Fig 3). Along with the PMB1 acyl tails, these hydrophobic residues drove the insertion process, as the AMPs penetrated further into the membrane over hundreds of nanoseconds. The DAB residues were observed to drag some water molecules into the hydrophobic bilayer core (Fig 3); on average less than one water molecule was present in the PMB1 free membrane, compared to an average of seven being present during the last microsecond of simulation. Moreover, when we studied the radial distribution of solvent around DAB residues, despite being fully inserted within the non-polar acyl tail region, an average of three water molecules were still present within 0.35 nm of the DAB nitrogen atoms (Fig 3). After ~3.3 microseconds, the fatty acid tails of the PMB1 had penetrated as far down as the core of the membrane. We also noted that unlike the OM models, there was no obvious peptide aggregation in the IM model; the PMB1 peptides inserted as monomers. The interaction of PMB1 with the three membrane models is summarised in Fig 4. Quantitative analysis revealed the probability of inter-PMB1 fatty acid tail interaction was only 7% after ~3.3 μs compared to 22% during the initial 350 ns, prior to all the fatty acid tails becoming inserted.


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 PMB1 interaction with the three membrane models.The peptides are shown at the start (A, C and E) and end of (B, D and F) simulations of the asymmetric OM, the lipid A bilayer and the symmetric IM models respectively. Insertion into the lipid A bilayer and the model inner membrane is clearly visible in the panels D and F corresponding to the end of these simulations respectively. The colour scheme is consistent with the previous figures.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004180.g004: Summary of PMB1 interaction with the three membrane models.The peptides are shown at the start (A, C and E) and end of (B, D and F) simulations of the asymmetric OM, the lipid A bilayer and the symmetric IM models respectively. Insertion into the lipid A bilayer and the model inner membrane is clearly visible in the panels D and F corresponding to the end of these simulations respectively. The colour scheme is consistent with the previous figures.
Mentions: Within 100 ns of binding to the membrane surface, the fatty acid tails of all of the PMB1 peptides inserted into the hydrophobic core of the bilayer. We observed that the D-Phe residues of the peptides also became embedded within the acyl tail region of the membrane within this timeframe (Fig 3). Along with the PMB1 acyl tails, these hydrophobic residues drove the insertion process, as the AMPs penetrated further into the membrane over hundreds of nanoseconds. The DAB residues were observed to drag some water molecules into the hydrophobic bilayer core (Fig 3); on average less than one water molecule was present in the PMB1 free membrane, compared to an average of seven being present during the last microsecond of simulation. Moreover, when we studied the radial distribution of solvent around DAB residues, despite being fully inserted within the non-polar acyl tail region, an average of three water molecules were still present within 0.35 nm of the DAB nitrogen atoms (Fig 3). After ~3.3 microseconds, the fatty acid tails of the PMB1 had penetrated as far down as the core of the membrane. We also noted that unlike the OM models, there was no obvious peptide aggregation in the IM model; the PMB1 peptides inserted as monomers. The interaction of PMB1 with the three membrane models is summarised in Fig 4. Quantitative analysis revealed the probability of inter-PMB1 fatty acid tail interaction was only 7% after ~3.3 μs compared to 22% during the initial 350 ns, prior to all the fatty acid tails becoming inserted.

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