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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

Left panel: schematic of a whole bacterial cell model. Protegrin pores (in red on the orange cell membrane) induce rapid transport of potassium (cyan spheres) and sodium (orange spheres) ions outside and inside the cell, respectively. From [11] with permission. Right panel: Potassium release curves for multiple values of the number of pores, along with experimental data. From [10] with permission.
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f7-ijms-13-11000: Left panel: schematic of a whole bacterial cell model. Protegrin pores (in red on the orange cell membrane) induce rapid transport of potassium (cyan spheres) and sodium (orange spheres) ions outside and inside the cell, respectively. From [11] with permission. Right panel: Potassium release curves for multiple values of the number of pores, along with experimental data. From [10] with permission.

Mentions: Our success in modeling the single-channel conductance of protegrin pores led us to ask what the effects of such pores would be on an entire cell. Using the single-pore conductance obtained from our PNP model, we have constructed a larger scale model that yields the time-dependent ion concentration in bacterial cells [10]. This model treats the bacterial interior and surrounding bath as well-mixed volumes with respect to ion diffusion, which allows for a simple, space-independent description of transport. The total flux of each ionic species is a function of the single-pore permeability values, which are obtained from the 3D-PNP calculations discussed above, as well as the number of pores, which is treated as a variable parameter. The model is described in detail in [10]. By adjusting only the number of pores in our model, we were able to match experimentally measured potassium leakage data from live exponential-phase E. coli, and thus provide the first estimate of the number of pores required to kill an E. coli cell—approximately one hundred. Potassium release curves are shown in Figure 7 below for different numbers of pores.


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

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

Left panel: schematic of a whole bacterial cell model. Protegrin pores (in red on the orange cell membrane) induce rapid transport of potassium (cyan spheres) and sodium (orange spheres) ions outside and inside the cell, respectively. From [11] with permission. Right panel: Potassium release curves for multiple values of the number of pores, along with experimental data. From [10] with permission.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7-ijms-13-11000: Left panel: schematic of a whole bacterial cell model. Protegrin pores (in red on the orange cell membrane) induce rapid transport of potassium (cyan spheres) and sodium (orange spheres) ions outside and inside the cell, respectively. From [11] with permission. Right panel: Potassium release curves for multiple values of the number of pores, along with experimental data. From [10] with permission.
Mentions: Our success in modeling the single-channel conductance of protegrin pores led us to ask what the effects of such pores would be on an entire cell. Using the single-pore conductance obtained from our PNP model, we have constructed a larger scale model that yields the time-dependent ion concentration in bacterial cells [10]. This model treats the bacterial interior and surrounding bath as well-mixed volumes with respect to ion diffusion, which allows for a simple, space-independent description of transport. The total flux of each ionic species is a function of the single-pore permeability values, which are obtained from the 3D-PNP calculations discussed above, as well as the number of pores, which is treated as a variable parameter. The model is described in detail in [10]. By adjusting only the number of pores in our model, we were able to match experimentally measured potassium leakage data from live exponential-phase E. coli, and thus provide the first estimate of the number of pores required to kill an E. coli cell—approximately one hundred. Potassium release curves are shown in Figure 7 below for different numbers of pores.

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