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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 pore structures calculated by the HOLE program(48) embedded in the averaged channel conformations during the simulations for the 12-, 16-, 20-, 24-, and 36-mer p3 (Aβ17−42) channels. The 12-, 16-, 20-, and 36-mer structures were obtained from the simulations in the zwitterionic DOPC bilayer. The 24-mer structure was obtained from the anionic bilayer containing POPC and POPG with a molar ratio of 4:1. In the angle views of the pore structure (upper row), whole channel structures are shown with the ribbon representation with the same color representations described in Figure 2. In the lateral views of the pore structure (lower row), cross-sectioned channels are given in the surface representation with the same color representations used in Figure 2. For the pore structures in the surface representation, the degree of the pore diameter is indicated by the color codes in the order of red < green < blue, but the scale of these colors is relative to each channel.
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fig4: Averaged pore structures calculated by the HOLE program(48) embedded in the averaged channel conformations during the simulations for the 12-, 16-, 20-, 24-, and 36-mer p3 (Aβ17−42) channels. The 12-, 16-, 20-, and 36-mer structures were obtained from the simulations in the zwitterionic DOPC bilayer. The 24-mer structure was obtained from the anionic bilayer containing POPC and POPG with a molar ratio of 4:1. In the angle views of the pore structure (upper row), whole channel structures are shown with the ribbon representation with the same color representations described in Figure 2. In the lateral views of the pore structure (lower row), cross-sectioned channels are given in the surface representation with the same color representations used in Figure 2. For the pore structures in the surface representation, the degree of the pore diameter is indicated by the color codes in the order of red < green < blue, but the scale of these colors is relative to each channel.

Mentions: The p3 channels increase their outer and inner pore diameters during the simulations. Figure 4 shows the averaged channel structures for all simulated sizes. The averaged pore structures are calculated by the HOLE program.(48) For the intermediate 16-, 20-, and 24-mer channels, the outer diameter of the simulated channels range between ∼6.9 and 8.0 nm, and the pore diameter ranges between ∼1.7 and 2.5 nm. Recent AFM images(27) show that for both p3 and N9 channels, the outer and inner diameter of the channels are ∼6−10 nm and ∼1−2 nm, respectively, consistent with the simulations. However, the 12-mer pore diameter is smaller (∼0.8 nm), and the 36-mer pore diameter (∼3.9 nm) is too large compared with experimental channels, although their outer dimensions are in the experimental range. The morphological features of the various p3 channels structures are similar to those of the N9 channels, although the details differ.(31)


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 pore structures calculated by the HOLE program(48) embedded in the averaged channel conformations during the simulations for the 12-, 16-, 20-, 24-, and 36-mer p3 (Aβ17−42) channels. The 12-, 16-, 20-, and 36-mer structures were obtained from the simulations in the zwitterionic DOPC bilayer. The 24-mer structure was obtained from the anionic bilayer containing POPC and POPG with a molar ratio of 4:1. In the angle views of the pore structure (upper row), whole channel structures are shown with the ribbon representation with the same color representations described in Figure 2. In the lateral views of the pore structure (lower row), cross-sectioned channels are given in the surface representation with the same color representations used in Figure 2. For the pore structures in the surface representation, the degree of the pore diameter is indicated by the color codes in the order of red < green < blue, but the scale of these colors is relative to each channel.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Averaged pore structures calculated by the HOLE program(48) embedded in the averaged channel conformations during the simulations for the 12-, 16-, 20-, 24-, and 36-mer p3 (Aβ17−42) channels. The 12-, 16-, 20-, and 36-mer structures were obtained from the simulations in the zwitterionic DOPC bilayer. The 24-mer structure was obtained from the anionic bilayer containing POPC and POPG with a molar ratio of 4:1. In the angle views of the pore structure (upper row), whole channel structures are shown with the ribbon representation with the same color representations described in Figure 2. In the lateral views of the pore structure (lower row), cross-sectioned channels are given in the surface representation with the same color representations used in Figure 2. For the pore structures in the surface representation, the degree of the pore diameter is indicated by the color codes in the order of red < green < blue, but the scale of these colors is relative to each channel.
Mentions: The p3 channels increase their outer and inner pore diameters during the simulations. Figure 4 shows the averaged channel structures for all simulated sizes. The averaged pore structures are calculated by the HOLE program.(48) For the intermediate 16-, 20-, and 24-mer channels, the outer diameter of the simulated channels range between ∼6.9 and 8.0 nm, and the pore diameter ranges between ∼1.7 and 2.5 nm. Recent AFM images(27) show that for both p3 and N9 channels, the outer and inner diameter of the channels are ∼6−10 nm and ∼1−2 nm, respectively, consistent with the simulations. However, the 12-mer pore diameter is smaller (∼0.8 nm), and the 36-mer pore diameter (∼3.9 nm) is too large compared with experimental channels, although their outer dimensions are in the experimental range. The morphological features of the various p3 channels structures are similar to those of the N9 channels, although the details differ.(31)

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