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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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Related in: MedlinePlus

Snapshot from molecular dynamics simulations of an antimicrobial peptide pore (peptides are shown in green) inside a cell membrane (lipid headgroups are shown in red and lipid acyl chains in gray). When a pore is formed, vital sodium and chloride ions (blue and red spheres) move in and out of cells too fast for bacteria to respond, leading to cell death. Computer simulations can provide structural and dynamic information of the relevant transport phenomena impossible to achieve with current experimental methods.
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f5-ijms-13-11000: Snapshot from molecular dynamics simulations of an antimicrobial peptide pore (peptides are shown in green) inside a cell membrane (lipid headgroups are shown in red and lipid acyl chains in gray). When a pore is formed, vital sodium and chloride ions (blue and red spheres) move in and out of cells too fast for bacteria to respond, leading to cell death. Computer simulations can provide structural and dynamic information of the relevant transport phenomena impossible to achieve with current experimental methods.

Mentions: Our first foray into the investigation of these structures consisted of fully atomistic MD simulations of an octameric protegrin pore embedded in a lipid bilayer [9]. The starting structure for these simulations was based on NMR experiments reported by Mani et al. [21], which suggest that protegrin pores are most likely composed of four parallel dimers. We first started with simulating monomeric and dimeric structures in various membrane mimic environments [22–40]. Ultimately, we simulated the pore structure for more than 150 ns, and found it to be indeed stable, with good agreement between NMR-derived inter-peptide distances and corresponding simulation data (Figure 5). Our simulation showed that the pore opening is large enough to readily conduct anions, but rarely allows cations to pass through due to the large positive charges of the peptides.


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

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

Snapshot from molecular dynamics simulations of an antimicrobial peptide pore (peptides are shown in green) inside a cell membrane (lipid headgroups are shown in red and lipid acyl chains in gray). When a pore is formed, vital sodium and chloride ions (blue and red spheres) move in and out of cells too fast for bacteria to respond, leading to cell death. Computer simulations can provide structural and dynamic information of the relevant transport phenomena impossible to achieve with current experimental methods.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5-ijms-13-11000: Snapshot from molecular dynamics simulations of an antimicrobial peptide pore (peptides are shown in green) inside a cell membrane (lipid headgroups are shown in red and lipid acyl chains in gray). When a pore is formed, vital sodium and chloride ions (blue and red spheres) move in and out of cells too fast for bacteria to respond, leading to cell death. Computer simulations can provide structural and dynamic information of the relevant transport phenomena impossible to achieve with current experimental methods.
Mentions: Our first foray into the investigation of these structures consisted of fully atomistic MD simulations of an octameric protegrin pore embedded in a lipid bilayer [9]. The starting structure for these simulations was based on NMR experiments reported by Mani et al. [21], which suggest that protegrin pores are most likely composed of four parallel dimers. We first started with simulating monomeric and dimeric structures in various membrane mimic environments [22–40]. Ultimately, we simulated the pore structure for more than 150 ns, and found it to be indeed stable, with good agreement between NMR-derived inter-peptide distances and corresponding simulation data (Figure 5). Our simulation showed that the pore opening is large enough to readily conduct anions, but rarely allows cations to pass through due to the large positive charges of the peptides.

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