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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 inner membrane.A- Water penetration into the inner membrane. (PMB1 non-tail regions: cyan, licorice format, PMB1 tails: cyan, VdW format, DAB: green, licorice format, lipid phosphate groups: orange, VdW format, phospholipids: orange, lines, water: dark red, VdW format). B- Mass density of the inner membrane system, showing the difference between PMB1 free (dotted lines) system and the system after being exposed to PMB1 for 3345 ns (full lines). C & D- Bilayer thickness analysis showing the correlation between PMB1 binding regions and membrane thinning (blue represents thinner areas and red thicker areas), along with an overview of the inner membrane after 3345 ns with PMB1 present (PMB1 and membrane are colored as previously).
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pcbi.1004180.g003: Summary of interactions with the inner membrane.A- Water penetration into the inner membrane. (PMB1 non-tail regions: cyan, licorice format, PMB1 tails: cyan, VdW format, DAB: green, licorice format, lipid phosphate groups: orange, VdW format, phospholipids: orange, lines, water: dark red, VdW format). B- Mass density of the inner membrane system, showing the difference between PMB1 free (dotted lines) system and the system after being exposed to PMB1 for 3345 ns (full lines). C & D- Bilayer thickness analysis showing the correlation between PMB1 binding regions and membrane thinning (blue represents thinner areas and red thicker areas), along with an overview of the inner membrane after 3345 ns with PMB1 present (PMB1 and membrane are colored as previously).

Mentions: As with the two OM models, to monitor the process of PMB1 binding to the IM, we set up two independent simulations. Each system was comprised of six PMB1 peptides initially placed in the bulk water region at a distance of ~0.5 nm from one leaflet (Sim_OM6). In both simulations a maximum of five PMB1 molecules were observed to bind to the membrane. Remaining solvent-phase PMB1 molecules were deleted before extending the simulation to 600 ns. An additional seven peptides were then added to the system, giving an overall total of 12 peptides, (Sim_OM12), and intermittently repositioned to ease membrane binding over 3 simulations (> 745 ns). After this, a total of seven PMB1 molecules had bound, and the membrane was judged to be saturated. The unbound peptides were removed and the simulation was extended for a final 2 microseconds (Sim_IM7). Hydrogen bonding interactions were formed between the DAB residues of the peptide and the phospholipid headgroups within a few nanoseconds. As with the two OM systems, we observed that the DAB residues acted as a “landing platform” at the IM surface. The side chains accounted for 46% (S1 Table) of the total hydrogen bonds formed between the whole PMB1 molecules and the lipid headgroups. After PMB1 insertion into the membrane core however, this value dropped dramatically and DAB accounted for only 17% of hydrogen bonds formed between the entire PMB1 molecule and the lipid headgroups. This was due to spontaneous insertion of the PMB1 tail into the hydrophobic portion of the membrane, leaving a large portion of the PMB1 ring structure also buried below the lipid headgroup region, and hence unable to form hydrogen bonds (Fig 3).


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 inner membrane.A- Water penetration into the inner membrane. (PMB1 non-tail regions: cyan, licorice format, PMB1 tails: cyan, VdW format, DAB: green, licorice format, lipid phosphate groups: orange, VdW format, phospholipids: orange, lines, water: dark red, VdW format). B- Mass density of the inner membrane system, showing the difference between PMB1 free (dotted lines) system and the system after being exposed to PMB1 for 3345 ns (full lines). C & D- Bilayer thickness analysis showing the correlation between PMB1 binding regions and membrane thinning (blue represents thinner areas and red thicker areas), along with an overview of the inner membrane after 3345 ns with PMB1 present (PMB1 and membrane are colored as previously).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004180.g003: Summary of interactions with the inner membrane.A- Water penetration into the inner membrane. (PMB1 non-tail regions: cyan, licorice format, PMB1 tails: cyan, VdW format, DAB: green, licorice format, lipid phosphate groups: orange, VdW format, phospholipids: orange, lines, water: dark red, VdW format). B- Mass density of the inner membrane system, showing the difference between PMB1 free (dotted lines) system and the system after being exposed to PMB1 for 3345 ns (full lines). C & D- Bilayer thickness analysis showing the correlation between PMB1 binding regions and membrane thinning (blue represents thinner areas and red thicker areas), along with an overview of the inner membrane after 3345 ns with PMB1 present (PMB1 and membrane are colored as previously).
Mentions: As with the two OM models, to monitor the process of PMB1 binding to the IM, we set up two independent simulations. Each system was comprised of six PMB1 peptides initially placed in the bulk water region at a distance of ~0.5 nm from one leaflet (Sim_OM6). In both simulations a maximum of five PMB1 molecules were observed to bind to the membrane. Remaining solvent-phase PMB1 molecules were deleted before extending the simulation to 600 ns. An additional seven peptides were then added to the system, giving an overall total of 12 peptides, (Sim_OM12), and intermittently repositioned to ease membrane binding over 3 simulations (> 745 ns). After this, a total of seven PMB1 molecules had bound, and the membrane was judged to be saturated. The unbound peptides were removed and the simulation was extended for a final 2 microseconds (Sim_IM7). Hydrogen bonding interactions were formed between the DAB residues of the peptide and the phospholipid headgroups within a few nanoseconds. As with the two OM systems, we observed that the DAB residues acted as a “landing platform” at the IM surface. The side chains accounted for 46% (S1 Table) of the total hydrogen bonds formed between the whole PMB1 molecules and the lipid headgroups. After PMB1 insertion into the membrane core however, this value dropped dramatically and DAB accounted for only 17% of hydrogen bonds formed between the entire PMB1 molecule and the lipid headgroups. This was due to spontaneous insertion of the PMB1 tail into the hydrophobic portion of the membrane, leaving a large portion of the PMB1 ring structure also buried below the lipid headgroup region, and hence unable to form hydrogen bonds (Fig 3).

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