Publisher Correction: Impact of alloy fluctuations and Coulomb effects on the electronic and optical properties of c-plane GaN/AlGaN quantum wells.

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The effect of membrane curvature on the conformation of antimicrobial peptides: implications for binding and the mechanism of action

Short cationic antimicrobial peptides (AMPs) are believed to act either by inducing transmembrane pores or disrupting membranes in a detergent-like manner. For example, the antimicrobial peptides aurein 1.2, citropin 1.1, maculatin 1.1 and caerin 1.1, despite being closely related, appear to act by fundamentally different mechanisms depending on their length. Using molecular dynamics simulations, the structural properties of these four peptides have been examined in solution as well as in a variety of membrane environments. It is shown that each of the peptides has a strong preference for binding to regions of high membrane curvature and that the structure of the peptides is dependent on the degree of local curvature. This suggests that the shorter peptides aurein 1.2 and citropin 1.1 act via a detergent-like mechanism because they can induce high local, but not long-range curvature, whereas the longer peptides maculatin 1.1 and caerin 1.1 require longer range curvature to fold and thus bind to and stabilize transmembrane pores

Escherichia coli Cell Surface Perturbation and Disruption Induced by Antimicrobial Peptides BP100 and pepR*

The potential of antimicrobial peptides (AMPs) as an alternative to conventional therapies is well recognized. Insights into the biological and biophysical properties of AMPs are thus key to understanding their mode of action. In this study, the mechanisms adopted by two AMPs in disrupting the Gram-negative Escherichia coli bacterial envelope were explored. BP100 is a short cecropin A-melittin hybrid peptide known to inhibit the growth of phytopathogenic Gram-negative bacteria. pepR, on the other hand, is a novel AMP derived from the dengue virus capsid protein. Both BP100 and pepR were found to inhibit the growth of E. coli at micromolar concentrations. Zeta potential measurements of E. coli incubated with increasing peptide concentrations allowed for the establishment of a correlation between the minimal inhibitory concentration (MIC) of each AMP and membrane surface charge neutralization. While a neutralization-mediated killing mechanism adopted by either AMP is not necessarily implied, the hypothesis that surface neutralization occurs close to MIC values was confirmed. Atomic force microscopy (AFM) was then employed to visualize the structural effect of the interaction of each AMP with the E. coli cell envelope. At their MICs, BP100 and pepR progressively destroyed the bacterial envelope, with extensive damage already occurring 2 h after peptide addition to the bacteria. A similar effect was observed for each AMP in the concentration-dependent studies. At peptide concentrations below MIC values, only minor disruptions of the bacterial surface occurred

Models of Toxic β-Sheet Channels of Protegrin-1 Suggest a Common Subunit Organization Motif Shared with Toxic Alzheimer β-Amyloid Ion Channels

Antimicrobial peptides (AMPs) induce cytotoxicity by altering membrane permeability. The electrical properties of membrane-associated AMPs as well as their cellular effects have been extensively documented; however their three-dimensional structure is poorly understood. Gaining insight into channel structures is important to the understanding of the protegrin-1 (PG-1) and other AMP cytolytic mechanisms, and to antibiotics design. We studied the β-sheet channels morphology using molecular dynamics simulations. We modeled PG-1 channels as intrinsic barrel-stave and toroidal membrane pores, and simulated them in zwitterionic and anionic lipid bilayers. PG-1 channels consist of eight β-hairpins in a consecutive NCCN (N and C represent the β-hairpin's N- and C-termini) packing organization yielding antiparallel and parallel β-sheet channels. Both channels preserve the toroidal, but not the barrel-stave pores. The two lipid leaflets of the bilayer bend toward each other at the channels' edges, producing a semitoroidal pore with the outward-pointing hydrophobic residues preventing the polar lipid headgroups from moving to the bilayer center. In all simulated lipid environments, PG-1 channels divide into four or five β-sheet subunits consisting of single or dimeric β-hairpins. The channel morphology with subunit organization is consistent with the four to five subunits observed by NMR in the POPE/POPG bilayer. Remarkably, a β-sheet subunit channel motif is in agreement with Alzheimer ion channels modeled using the universal U-shape β-strand-turn-β-strand structure, as well as with high resolution atomic force microscopy images of β-amyloid channels with four to six subunits. Consistent with the toxic β-amyloid channels that are ion-conducting, the PG-1 channels permeate anions

Models of Toxic β-Sheet Channels of Protegrin-1 Suggest a Common Subunit Organization Motif Shared with Toxic Alzheimer β-Amyloid Ion Channels

Antimicrobial peptides (AMPs) induce cytotoxicity by altering membrane permeability. The electrical properties of membrane-associated AMPs as well as their cellular effects have been extensively documented; however their three-dimensional structure is poorly understood. Gaining insight into channel structures is important to the understanding of the protegrin-1 (PG-1) and other AMP cytolytic mechanisms, and to antibiotics design. We studied the β-sheet channels morphology using molecular dynamics simulations. We modeled PG-1 channels as intrinsic barrel-stave and toroidal membrane pores, and simulated them in zwitterionic and anionic lipid bilayers. PG-1 channels consist of eight β-hairpins in a consecutive NCCN (N and C represent the β-hairpin's N- and C-termini) packing organization yielding antiparallel and parallel β-sheet channels. Both channels preserve the toroidal, but not the barrel-stave pores. The two lipid leaflets of the bilayer bend toward each other at the channels' edges, producing a semitoroidal pore with the outward-pointing hydrophobic residues preventing the polar lipid headgroups from moving to the bilayer center. In all simulated lipid environments, PG-1 channels divide into four or five β-sheet subunits consisting of single or dimeric β-hairpins. The channel morphology with subunit organization is consistent with the four to five subunits observed by NMR in the POPE/POPG bilayer. Remarkably, a β-sheet subunit channel motif is in agreement with Alzheimer ion channels modeled using the universal U-shape β-strand-turn-β-strand structure, as well as with high resolution atomic force microscopy images of β-amyloid channels with four to six subunits. Consistent with the toxic β-amyloid channels that are ion-conducting, the PG-1 channels permeate anions

Misfolded Amyloid Ion Channels Present Mobile β-Sheet Subunits in Contrast to Conventional Ion Channels

In Alzheimer's disease, calcium permeability through cellular membranes appears to underlie neuronal cell death. It is increasingly accepted that calcium permeability involves toxic ion channels. We modeled Alzheimer's disease ion channels of different sizes (12-mer to 36-mer) in the lipid bilayer using molecular dynamics simulations. Our Aβ channels consist of the solid-state NMR-based U-shaped β-strand-turn-β-strand motif. In the simulations we obtain ion-permeable channels whose subunit morphologies and shapes are consistent with electron microscopy/atomic force microscopy. In agreement with imaged channels, the simulations indicate that β-sheet channels break into loosely associated mobile β-sheet subunits. The preferred channel sizes (16- to 24-mer) are compatible with electron microscopy/atomic force microscopy-derived dimensions. Mobile subunits were also observed for β-sheet channels formed by cytolytic PG-1 β-hairpins. The emerging picture from our large-scale simulations is that toxic ion channels formed by β-sheets spontaneously break into loosely interacting dynamic units that associate and dissociate leading to toxic ionic flux. This sharply contrasts intact conventional gated ion channels that consist of tightly interacting α-helices that robustly prevent ion leakage, rather than hydrogen-bonded β-strands. The simulations suggest why conventional gated channels evolved to consist of interacting α-helices rather than hydrogen-bonded β-strands that tend to break in fluidic bilayers. Nature designs folded channels but not misfolded toxic channels