Limits...
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 outer membrane.A & B- Snapshots showing the starting (time = 0 microseconds) and final (time = 2 microseconds) configurations of the asymmetric membrane model systems. (PMB1 non- tail regions: cyan, licorice format, PMB1 tails: cyan, VdW format, lipid phosphate groups: orange, VdW format, LPS sugars: lime, lines format, LPS phospholipids: orange, lines format). C- Hydrogen bonding interactions between PMB1 and the LPS sugars, colored as above with DAB residues: purple, licorice format. D- Aggregation of PMB1 on the LPS surface, colored as above, but with LPS tails: orange, VdW format
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4401565&req=5

pcbi.1004180.g001: Summary of interactions with the outer membrane.A & B- Snapshots showing the starting (time = 0 microseconds) and final (time = 2 microseconds) configurations of the asymmetric membrane model systems. (PMB1 non- tail regions: cyan, licorice format, PMB1 tails: cyan, VdW format, lipid phosphate groups: orange, VdW format, LPS sugars: lime, lines format, LPS phospholipids: orange, lines format). C- Hydrogen bonding interactions between PMB1 and the LPS sugars, colored as above with DAB residues: purple, licorice format. D- Aggregation of PMB1 on the LPS surface, colored as above, but with LPS tails: orange, VdW format

Mentions: In each of the simulations, the first peptides were observed to interact with the LPS sugars within only a few nanoseconds, where interaction is defined as atoms ≤0.35 nm apart, (Fig 1). As demonstrated by the sudden drop in solvent accessible surface area, and by monitoring the mean centre of mass coordinate of the peptides along the z-axis (i.e. membrane normal) (S1 Fig and S2 Fig), the majority of the PMB1 molecules became bound within ~200 ns. Moreover, the component centre of mass analysis reveals that the DAB residues are largely responsible for the initial binding process, acting as a “landing platform” prior to the remainder of the PMB1 adsorption process, consistent with previously reported fluorescence studies (S3 Fig) [12, 13].


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 outer membrane.A & B- Snapshots showing the starting (time = 0 microseconds) and final (time = 2 microseconds) configurations of the asymmetric membrane model systems. (PMB1 non- tail regions: cyan, licorice format, PMB1 tails: cyan, VdW format, lipid phosphate groups: orange, VdW format, LPS sugars: lime, lines format, LPS phospholipids: orange, lines format). C- Hydrogen bonding interactions between PMB1 and the LPS sugars, colored as above with DAB residues: purple, licorice format. D- Aggregation of PMB1 on the LPS surface, colored as above, but with LPS tails: orange, VdW format
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004180.g001: Summary of interactions with the outer membrane.A & B- Snapshots showing the starting (time = 0 microseconds) and final (time = 2 microseconds) configurations of the asymmetric membrane model systems. (PMB1 non- tail regions: cyan, licorice format, PMB1 tails: cyan, VdW format, lipid phosphate groups: orange, VdW format, LPS sugars: lime, lines format, LPS phospholipids: orange, lines format). C- Hydrogen bonding interactions between PMB1 and the LPS sugars, colored as above with DAB residues: purple, licorice format. D- Aggregation of PMB1 on the LPS surface, colored as above, but with LPS tails: orange, VdW format
Mentions: In each of the simulations, the first peptides were observed to interact with the LPS sugars within only a few nanoseconds, where interaction is defined as atoms ≤0.35 nm apart, (Fig 1). As demonstrated by the sudden drop in solvent accessible surface area, and by monitoring the mean centre of mass coordinate of the peptides along the z-axis (i.e. membrane normal) (S1 Fig and S2 Fig), the majority of the PMB1 molecules became bound within ~200 ns. Moreover, the component centre of mass analysis reveals that the DAB residues are largely responsible for the initial binding process, acting as a “landing platform” prior to the remainder of the PMB1 adsorption process, consistent with previously reported fluorescence studies (S3 Fig) [12, 13].

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