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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

Averaged peptide interaction energy with ions in the simulations for the 16-, 20-, and 24-mer p3 (Aβ17−42) channels. The interaction energies for the 16- and 20-mer were obtained from the simulations in the zwitterionic DOPC bilayer. The interaction energy for the 24-mer was obtained from the anionic bilayer containing POPC and POPG at a molar ratio of 4:1.
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fig8: Averaged peptide interaction energy with ions in the simulations for the 16-, 20-, and 24-mer p3 (Aβ17−42) channels. The interaction energies for the 16- and 20-mer were obtained from the simulations in the zwitterionic DOPC bilayer. The interaction energy for the 24-mer was obtained from the anionic bilayer containing POPC and POPG at a molar ratio of 4:1.

Mentions: The interactions of the peptides with ions may suggest different binding affinities for ions in the pore. We calculated the interaction energy for each peptide with ions and then averaged the peptide interaction energy over time and the number of peptides in the channel (Figure 8). The peptide interaction energies suggest that, as expected, peptide interactions with K+ and Cl− are weak since both K+ and Cl− have a single charge. For double-charged ions Mg2+, Ca2+, and Zn2+, relatively strong peptide interactions with those ions can be observed due to the strong electrostatic attraction. The p3 peptides favor interaction with the ions in the order of Zn2+ > Ca2+ > Mg2+ > K+ ≈ Cl−. Strong peptide interaction with Zn2+ indicates that Zn2+ blocks the binding sites, preventing the other cations getting into the pore. It has been noted that Zn2+ inhibits Aβ toxicity, serving as channel blocker by reducing calcium transport.1−17,27


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)

Averaged peptide interaction energy with ions in the simulations for the 16-, 20-, and 24-mer p3 (Aβ17−42) channels. The interaction energies for the 16- and 20-mer were obtained from the simulations in the zwitterionic DOPC bilayer. The interaction energy for the 24-mer was obtained from the anionic bilayer containing POPC and POPG at a molar ratio of 4:1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig8: Averaged peptide interaction energy with ions in the simulations for the 16-, 20-, and 24-mer p3 (Aβ17−42) channels. The interaction energies for the 16- and 20-mer were obtained from the simulations in the zwitterionic DOPC bilayer. The interaction energy for the 24-mer was obtained from the anionic bilayer containing POPC and POPG at a molar ratio of 4:1.
Mentions: The interactions of the peptides with ions may suggest different binding affinities for ions in the pore. We calculated the interaction energy for each peptide with ions and then averaged the peptide interaction energy over time and the number of peptides in the channel (Figure 8). The peptide interaction energies suggest that, as expected, peptide interactions with K+ and Cl− are weak since both K+ and Cl− have a single charge. For double-charged ions Mg2+, Ca2+, and Zn2+, relatively strong peptide interactions with those ions can be observed due to the strong electrostatic attraction. The p3 peptides favor interaction with the ions in the order of Zn2+ > Ca2+ > Mg2+ > K+ ≈ Cl−. Strong peptide interaction with Zn2+ indicates that Zn2+ blocks the binding sites, preventing the other cations getting into the pore. It has been noted that Zn2+ inhibits Aβ toxicity, serving as channel blocker by reducing calcium transport.1−17,27

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