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Structural convergence among diverse, toxic beta-sheet ion channels.

Jang H, Teran Arce F, Ramachandran S, Capone R, Lal R, Nussinov R - J Phys Chem B (2010)

Bottom Line: However, the intriguing question of preferred channel sizes is still unresolved.Here, exploiting ssNMR-based, U-shaped, beta-strand-turn-beta-strand coordinates, we modeled truncated Abeta peptide (p3) channels with different sizes (12- to 36-mer).Molecular dynamics (MD) simulations show that optimal channel sizes of the ion channels presenting toxic ionic flux range between 16- and 24-mer.

View Article: PubMed Central - PubMed

Affiliation: Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA.

ABSTRACT
Recent studies show that an array of beta-sheet peptides, including N-terminally truncated Abeta peptides (Abeta(11-42/17-42)), K3 (a beta(2)-microglobulin fragment), and protegrin-1 (PG-1) peptides form ion channel-like structures and elicit single channel ion conductance when reconstituted in lipid bilayers and induce cell damage through cell calcium overload. Striking similarities are observed in the dimensions of these toxic channels irrespective of their amino acid sequences. However, the intriguing question of preferred channel sizes is still unresolved. Here, exploiting ssNMR-based, U-shaped, beta-strand-turn-beta-strand coordinates, we modeled truncated Abeta peptide (p3) channels with different sizes (12- to 36-mer). Molecular dynamics (MD) simulations show that optimal channel sizes of the ion channels presenting toxic ionic flux range between 16- and 24-mer. This observation is in good agreement with channel dimensions imaged by AFM for Abeta(9-42), K3 fragment, and PG-1 channels and highlights the bilayer-supported preferred toxic beta-channel sizes and organization, regardless of the peptide sequence.

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Related in: MedlinePlus

(a) Conceptual design of annular structure for the 20-mer p3 (Aβ17−42) channel and (b) the starting point of production run in the DOPC bilayer. Snapshots of the p3 channel taken at the simulation times of t = (c) 5, (d) 10, (e) 15, (f) 20, (g) 25, and (h) t = 30 ns. The cartoons representing the channel are in angle view with the same color representations described in Figure 2.
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fig3: (a) Conceptual design of annular structure for the 20-mer p3 (Aβ17−42) channel and (b) the starting point of production run in the DOPC bilayer. Snapshots of the p3 channel taken at the simulation times of t = (c) 5, (d) 10, (e) 15, (f) 20, (g) 25, and (h) t = 30 ns. The cartoons representing the channel are in angle view with the same color representations described in Figure 2.

Mentions: The designed channels have a perfectly annular shape in a void (Figure 2). In the initial annular structure, the pore-lining N-terminal strands form a β-sheet with intermolecular backbone H-bonds, which is not the case for the lipid-contacting outer C-terminal β-strands because of the larger curvature at the channel periphery (except the large 36-mer). The channels gradually relax in the lipid bilayer (Figure 3), and their optimized subunits can be observed after 5 ns (Figure 3c). The averaged peptide interaction energies for the peptide interactions with their surrounding environments, including other peptides, lipids, and water, reach equilibration at t > 10 ns (Figure S1), suggesting that the channels are fully relaxed in the lipid bilayers after the initial transient state. In our previous simulations for the same peptides in solution, double-layered U-shaped peptide interactions with matching the C-terminal hydrophobic sheet−sheet association produced the stable structures of linear(43) and annular(44) fibrils.


Structural convergence among diverse, toxic beta-sheet ion channels.

Jang H, Teran Arce F, Ramachandran S, Capone R, Lal R, Nussinov R - J Phys Chem B (2010)

(a) Conceptual design of annular structure for the 20-mer p3 (Aβ17−42) channel and (b) the starting point of production run in the DOPC bilayer. Snapshots of the p3 channel taken at the simulation times of t = (c) 5, (d) 10, (e) 15, (f) 20, (g) 25, and (h) t = 30 ns. The cartoons representing the channel are in angle view with the same color representations described in Figure 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2908347&req=5

fig3: (a) Conceptual design of annular structure for the 20-mer p3 (Aβ17−42) channel and (b) the starting point of production run in the DOPC bilayer. Snapshots of the p3 channel taken at the simulation times of t = (c) 5, (d) 10, (e) 15, (f) 20, (g) 25, and (h) t = 30 ns. The cartoons representing the channel are in angle view with the same color representations described in Figure 2.
Mentions: The designed channels have a perfectly annular shape in a void (Figure 2). In the initial annular structure, the pore-lining N-terminal strands form a β-sheet with intermolecular backbone H-bonds, which is not the case for the lipid-contacting outer C-terminal β-strands because of the larger curvature at the channel periphery (except the large 36-mer). The channels gradually relax in the lipid bilayer (Figure 3), and their optimized subunits can be observed after 5 ns (Figure 3c). The averaged peptide interaction energies for the peptide interactions with their surrounding environments, including other peptides, lipids, and water, reach equilibration at t > 10 ns (Figure S1), suggesting that the channels are fully relaxed in the lipid bilayers after the initial transient state. In our previous simulations for the same peptides in solution, double-layered U-shaped peptide interactions with matching the C-terminal hydrophobic sheet−sheet association produced the stable structures of linear(43) and annular(44) fibrils.

Bottom Line: However, the intriguing question of preferred channel sizes is still unresolved.Here, exploiting ssNMR-based, U-shaped, beta-strand-turn-beta-strand coordinates, we modeled truncated Abeta peptide (p3) channels with different sizes (12- to 36-mer).Molecular dynamics (MD) simulations show that optimal channel sizes of the ion channels presenting toxic ionic flux range between 16- and 24-mer.

View Article: PubMed Central - PubMed

Affiliation: Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA.

ABSTRACT
Recent studies show that an array of beta-sheet peptides, including N-terminally truncated Abeta peptides (Abeta(11-42/17-42)), K3 (a beta(2)-microglobulin fragment), and protegrin-1 (PG-1) peptides form ion channel-like structures and elicit single channel ion conductance when reconstituted in lipid bilayers and induce cell damage through cell calcium overload. Striking similarities are observed in the dimensions of these toxic channels irrespective of their amino acid sequences. However, the intriguing question of preferred channel sizes is still unresolved. Here, exploiting ssNMR-based, U-shaped, beta-strand-turn-beta-strand coordinates, we modeled truncated Abeta peptide (p3) channels with different sizes (12- to 36-mer). Molecular dynamics (MD) simulations show that optimal channel sizes of the ion channels presenting toxic ionic flux range between 16- and 24-mer. This observation is in good agreement with channel dimensions imaged by AFM for Abeta(9-42), K3 fragment, and PG-1 channels and highlights the bilayer-supported preferred toxic beta-channel sizes and organization, regardless of the peptide sequence.

Show MeSH
Related in: MedlinePlus