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Multiscale models of the antimicrobial peptide protegrin-1 on gram-negative bacteria membranes.

Bolintineanu DS, Vivcharuk V, Kaznessis YN - Int J Mol Sci (2012)

Bottom Line: We present a summary of computational investigations in our lab aimed at understanding this unique mechanism of action, in particular the development of models that provide a quantitative connection between molecular-level biophysical phenomena and relevant biological effects.Using fully atomistic molecular dynamics simulations, we have computed the thermodynamics of peptide-membrane association and insertion, as well as peptide aggregation.Overall, this work provides a quantitative mechanistic description of the mechanism of action of protegrin antimicrobial peptides across multiple length and time scales.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering and Materials Science, University of Minnesota, 421 Washington Ave SE, Minneapolis, MN 55455, USA; E-Mails: dan.bolintineanu@gmail.com (D.S.B.); vivch001@gmail.com (V.V.).

ABSTRACT
Antimicrobial peptides (AMPs) are naturally-occurring molecules that exhibit strong antibiotic properties against numerous infectious bacterial strains. Because of their unique mechanism of action, they have been touted as a potential source for novel antibiotic drugs. We present a summary of computational investigations in our lab aimed at understanding this unique mechanism of action, in particular the development of models that provide a quantitative connection between molecular-level biophysical phenomena and relevant biological effects. Our work is focused on protegrins, a potent class of AMPs that attack bacteria by associating with the bacterial membrane and forming transmembrane pores that facilitate the unrestricted transport of ions. Using fully atomistic molecular dynamics simulations, we have computed the thermodynamics of peptide-membrane association and insertion, as well as peptide aggregation. We also present a multi-scale analysis of the ion transport properties of protegrin pores, ranging from atomistic molecular dynamics simulations to mesoscale continuum models of single-pore electrodiffusion to models of transient ion transport from bacterial cells. Overall, this work provides a quantitative mechanistic description of the mechanism of action of protegrin antimicrobial peptides across multiple length and time scales.

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The different models of lipid topologies surrounding the PG-1 transmembrane pore. (A) The barrel-stave pore, where lipids retain their alignment with the bilayer normal; (B) The toroidal pore, where lipids tilt fully towards the pore to create a continuous leaflet that completely lines the outside of the pore; (C) The semi-toroidal pore, where lipids tilt partially towards the peptides, but do not form a continuous leaflet. From [11] with permission.
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f8-ijms-13-11000: The different models of lipid topologies surrounding the PG-1 transmembrane pore. (A) The barrel-stave pore, where lipids retain their alignment with the bilayer normal; (B) The toroidal pore, where lipids tilt fully towards the pore to create a continuous leaflet that completely lines the outside of the pore; (C) The semi-toroidal pore, where lipids tilt partially towards the peptides, but do not form a continuous leaflet. From [11] with permission.

Mentions: One important remaining question is related to the structure of lipids around the protegrin pore. Determining the structure of lipid bilayers is an important determinant of activity and specificity of protegrins. These antimicrobial peptides are known to be active against Gram negative bacteria but not so active against Gram positive bacteria. A hypothesis is that the lipid membranes of various bacteria have different compositions of lipid molecules that result in different energies for pore formation. In Figure 8, the three prevalent structures are shown. Although it is currently not clear how the lipid composition impacts the pore formation free energies, we believe that molecular simulations may provide useful insight into the molecular interactions than underlie antimicrobial peptide activity and specificity.


Multiscale models of the antimicrobial peptide protegrin-1 on gram-negative bacteria membranes.

Bolintineanu DS, Vivcharuk V, Kaznessis YN - Int J Mol Sci (2012)

The different models of lipid topologies surrounding the PG-1 transmembrane pore. (A) The barrel-stave pore, where lipids retain their alignment with the bilayer normal; (B) The toroidal pore, where lipids tilt fully towards the pore to create a continuous leaflet that completely lines the outside of the pore; (C) The semi-toroidal pore, where lipids tilt partially towards the peptides, but do not form a continuous leaflet. From [11] with permission.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472726&req=5

f8-ijms-13-11000: The different models of lipid topologies surrounding the PG-1 transmembrane pore. (A) The barrel-stave pore, where lipids retain their alignment with the bilayer normal; (B) The toroidal pore, where lipids tilt fully towards the pore to create a continuous leaflet that completely lines the outside of the pore; (C) The semi-toroidal pore, where lipids tilt partially towards the peptides, but do not form a continuous leaflet. From [11] with permission.
Mentions: One important remaining question is related to the structure of lipids around the protegrin pore. Determining the structure of lipid bilayers is an important determinant of activity and specificity of protegrins. These antimicrobial peptides are known to be active against Gram negative bacteria but not so active against Gram positive bacteria. A hypothesis is that the lipid membranes of various bacteria have different compositions of lipid molecules that result in different energies for pore formation. In Figure 8, the three prevalent structures are shown. Although it is currently not clear how the lipid composition impacts the pore formation free energies, we believe that molecular simulations may provide useful insight into the molecular interactions than underlie antimicrobial peptide activity and specificity.

Bottom Line: We present a summary of computational investigations in our lab aimed at understanding this unique mechanism of action, in particular the development of models that provide a quantitative connection between molecular-level biophysical phenomena and relevant biological effects.Using fully atomistic molecular dynamics simulations, we have computed the thermodynamics of peptide-membrane association and insertion, as well as peptide aggregation.Overall, this work provides a quantitative mechanistic description of the mechanism of action of protegrin antimicrobial peptides across multiple length and time scales.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering and Materials Science, University of Minnesota, 421 Washington Ave SE, Minneapolis, MN 55455, USA; E-Mails: dan.bolintineanu@gmail.com (D.S.B.); vivch001@gmail.com (V.V.).

ABSTRACT
Antimicrobial peptides (AMPs) are naturally-occurring molecules that exhibit strong antibiotic properties against numerous infectious bacterial strains. Because of their unique mechanism of action, they have been touted as a potential source for novel antibiotic drugs. We present a summary of computational investigations in our lab aimed at understanding this unique mechanism of action, in particular the development of models that provide a quantitative connection between molecular-level biophysical phenomena and relevant biological effects. Our work is focused on protegrins, a potent class of AMPs that attack bacteria by associating with the bacterial membrane and forming transmembrane pores that facilitate the unrestricted transport of ions. Using fully atomistic molecular dynamics simulations, we have computed the thermodynamics of peptide-membrane association and insertion, as well as peptide aggregation. We also present a multi-scale analysis of the ion transport properties of protegrin pores, ranging from atomistic molecular dynamics simulations to mesoscale continuum models of single-pore electrodiffusion to models of transient ion transport from bacterial cells. Overall, this work provides a quantitative mechanistic description of the mechanism of action of protegrin antimicrobial peptides across multiple length and time scales.

Show MeSH
Related in: MedlinePlus