Limits...
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.

Show MeSH

Related in: MedlinePlus

The proposed mechanism of action of Protegrin 1. Peptides (depicted in red ribbons, with the two disulfide bonds shown as yellow sticks) adsorb to the membrane surface (A), insert into the hydrophobic core in a transmembrane orientation (B), and form dimers (C). Peptide dimers oligomerize, likely as four or five pairs, to form water-filled, transmembrane pores (D) that lead to unrestricted ion transport and cell death. From [11] with permission.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1-ijms-13-11000: The proposed mechanism of action of Protegrin 1. Peptides (depicted in red ribbons, with the two disulfide bonds shown as yellow sticks) adsorb to the membrane surface (A), insert into the hydrophobic core in a transmembrane orientation (B), and form dimers (C). Peptide dimers oligomerize, likely as four or five pairs, to form water-filled, transmembrane pores (D) that lead to unrestricted ion transport and cell death. From [11] with permission.

Mentions: In order to provide a detailed analysis of the AMP mechanism of action, we have focused our efforts on protegrin, a particularly potent peptide initially isolated in pigs [4]. The balance of the evidence suggests that protegrin and many other AMPs act primarily by interacting with and disrupting the plasma membrane of bacteria [5–11]. As a result, a great deal of effort has been expended to investigate the interactions of AMPs with cell membranes as well as model lipid bilayer membranes. Protegrin 1 (PG-1) is an excellent model peptide because it has been the subject of numerous such studies, as well as having a promising therapeutic profile. The key steps in the bactericidal mechanism of action of PG-1 are summarized in Figure 1.


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 proposed mechanism of action of Protegrin 1. Peptides (depicted in red ribbons, with the two disulfide bonds shown as yellow sticks) adsorb to the membrane surface (A), insert into the hydrophobic core in a transmembrane orientation (B), and form dimers (C). Peptide dimers oligomerize, likely as four or five pairs, to form water-filled, transmembrane pores (D) that lead to unrestricted ion transport and cell death. 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

f1-ijms-13-11000: The proposed mechanism of action of Protegrin 1. Peptides (depicted in red ribbons, with the two disulfide bonds shown as yellow sticks) adsorb to the membrane surface (A), insert into the hydrophobic core in a transmembrane orientation (B), and form dimers (C). Peptide dimers oligomerize, likely as four or five pairs, to form water-filled, transmembrane pores (D) that lead to unrestricted ion transport and cell death. From [11] with permission.
Mentions: In order to provide a detailed analysis of the AMP mechanism of action, we have focused our efforts on protegrin, a particularly potent peptide initially isolated in pigs [4]. The balance of the evidence suggests that protegrin and many other AMPs act primarily by interacting with and disrupting the plasma membrane of bacteria [5–11]. As a result, a great deal of effort has been expended to investigate the interactions of AMPs with cell membranes as well as model lipid bilayer membranes. Protegrin 1 (PG-1) is an excellent model peptide because it has been the subject of numerous such studies, as well as having a promising therapeutic profile. The key steps in the bactericidal mechanism of action of PG-1 are summarized in Figure 1.

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