How can a beta-sheet peptide be both a potent antimicrobial and harmfully toxic? Molecular dynamics simulations of protegrin-1 in micelles

Allison A Langham, Himanshu Khandelia, Yiannis N Kaznessis

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

 
Udgivelsesdato: 2006-null
OriginalsprogEngelsk
TidsskriftBiopolymers
Vol/bind84
Udgave nummer2
Sider (fra-til)219-231
Antal sider12
ISSN0006-3525
DOI
StatusUdgivet - 1. jan. 2006

Fingeraftryk

Poisons
Micelles
Molecular Dynamics Simulation
Molecular dynamics
Peptides
Computer simulation
Membranes
protegrin-1
beta-Strand Protein Conformation
Toxicity
Arginine
Bacteria
Mirrors
Sodium
Atoms
Water

Bibliografisk note

Copyright 2005 Wiley Periodicals, Inc.

Citer dette

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title = "How can a beta-sheet peptide be both a potent antimicrobial and harmfully toxic? Molecular dynamics simulations of protegrin-1 in micelles",
abstract = "In this work, the naturally occurring beta-hairpin antimicrobial peptide protegrin-1 (PG-1) is studied by molecular dynamics simulation in all-atom sodium dodecylsulfate and dodecylphosphocholine micelles. These simulations provide a high-resolution picture of the interactions between the peptide and simple models of bacterial and mammalian membranes. Both micelles show significant disruption, as is expected for a peptide that is both active against bacteria and toxic to host cells. There is, however, clear differentiation between the behavior in SDS versus DPC, which suggests different mechanisms of interaction for PG-1 with mammalian and bacterial membranes. Specifically, the equilibrium orientation of the peptide relative to SDS is a mirror image of its position relative to DPC. In both systems, the arginine residues of PG-1 strongly interact with the head groups of the micelles. In DPC, the peptide prefers a location closer to the core of the micelle with Phe12, Val14, and Val16 imbedded in the core and the other side of the hairpin, which includes Leu5 and Tyr7, located closer to the surface of the micelle. In SDS, the peptide prefers a location at the micelle-water interface. The peptide position is reversed, with Leu5 and Cys6 imbedded furthest in the micelle core and Phe12, Val14, and Val16 on the surface of the micelle. We discuss the implications of these results with respect to activity and toxicity.",
keywords = "Amino Acid Sequence, Anti-Infective Agents, Antimicrobial Cationic Peptides, Arginine, Computer Simulation, Hydrophobicity, Micelles, Models, Molecular, Models, Structural, Peptides, Phosphorylcholine, Protein Structure, Secondary, Proteins, Sodium Dodecyl Sulfate, Water",
author = "Langham, {Allison A} and Himanshu Khandelia and Kaznessis, {Yiannis N}",
note = "Copyright 2005 Wiley Periodicals, Inc.",
year = "2006",
month = "1",
day = "1",
doi = "10.1002/bip.20397",
language = "English",
volume = "84",
pages = "219--231",
journal = "Biopolymers",
issn = "0006-3525",
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How can a beta-sheet peptide be both a potent antimicrobial and harmfully toxic? Molecular dynamics simulations of protegrin-1 in micelles. / Langham, Allison A; Khandelia, Himanshu; Kaznessis, Yiannis N.

I: Biopolymers, Bind 84, Nr. 2, 01.01.2006, s. 219-231.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - How can a beta-sheet peptide be both a potent antimicrobial and harmfully toxic? Molecular dynamics simulations of protegrin-1 in micelles

AU - Langham, Allison A

AU - Khandelia, Himanshu

AU - Kaznessis, Yiannis N

N1 - Copyright 2005 Wiley Periodicals, Inc.

PY - 2006/1/1

Y1 - 2006/1/1

N2 - In this work, the naturally occurring beta-hairpin antimicrobial peptide protegrin-1 (PG-1) is studied by molecular dynamics simulation in all-atom sodium dodecylsulfate and dodecylphosphocholine micelles. These simulations provide a high-resolution picture of the interactions between the peptide and simple models of bacterial and mammalian membranes. Both micelles show significant disruption, as is expected for a peptide that is both active against bacteria and toxic to host cells. There is, however, clear differentiation between the behavior in SDS versus DPC, which suggests different mechanisms of interaction for PG-1 with mammalian and bacterial membranes. Specifically, the equilibrium orientation of the peptide relative to SDS is a mirror image of its position relative to DPC. In both systems, the arginine residues of PG-1 strongly interact with the head groups of the micelles. In DPC, the peptide prefers a location closer to the core of the micelle with Phe12, Val14, and Val16 imbedded in the core and the other side of the hairpin, which includes Leu5 and Tyr7, located closer to the surface of the micelle. In SDS, the peptide prefers a location at the micelle-water interface. The peptide position is reversed, with Leu5 and Cys6 imbedded furthest in the micelle core and Phe12, Val14, and Val16 on the surface of the micelle. We discuss the implications of these results with respect to activity and toxicity.

AB - In this work, the naturally occurring beta-hairpin antimicrobial peptide protegrin-1 (PG-1) is studied by molecular dynamics simulation in all-atom sodium dodecylsulfate and dodecylphosphocholine micelles. These simulations provide a high-resolution picture of the interactions between the peptide and simple models of bacterial and mammalian membranes. Both micelles show significant disruption, as is expected for a peptide that is both active against bacteria and toxic to host cells. There is, however, clear differentiation between the behavior in SDS versus DPC, which suggests different mechanisms of interaction for PG-1 with mammalian and bacterial membranes. Specifically, the equilibrium orientation of the peptide relative to SDS is a mirror image of its position relative to DPC. In both systems, the arginine residues of PG-1 strongly interact with the head groups of the micelles. In DPC, the peptide prefers a location closer to the core of the micelle with Phe12, Val14, and Val16 imbedded in the core and the other side of the hairpin, which includes Leu5 and Tyr7, located closer to the surface of the micelle. In SDS, the peptide prefers a location at the micelle-water interface. The peptide position is reversed, with Leu5 and Cys6 imbedded furthest in the micelle core and Phe12, Val14, and Val16 on the surface of the micelle. We discuss the implications of these results with respect to activity and toxicity.

KW - Amino Acid Sequence

KW - Anti-Infective Agents

KW - Antimicrobial Cationic Peptides

KW - Arginine

KW - Computer Simulation

KW - Hydrophobicity

KW - Micelles

KW - Models, Molecular

KW - Models, Structural

KW - Peptides

KW - Phosphorylcholine

KW - Protein Structure, Secondary

KW - Proteins

KW - Sodium Dodecyl Sulfate

KW - Water

U2 - 10.1002/bip.20397

DO - 10.1002/bip.20397

M3 - Journal article

C2 - 16235232

VL - 84

SP - 219

EP - 231

JO - Biopolymers

JF - Biopolymers

SN - 0006-3525

IS - 2

ER -