Limits...
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.

Show MeSH

Related in: MedlinePlus

Parameters to define the subunits for the 20-mer p3 (Aβ17−42) channel: (a) mapping of x, y coordinates of the β-strands of each peptide onto the x−y plane, (b) the description of secondary structure by STRIDE,(49) (c) the β-strand order parameter Sβ-strand, (d) the averaged β-strand B-factor, and (e) percent of β-sheet content. In the β-strands mapping, the contour lines enclose the high-frequency regions in the order of red < orange < yellow < green < blue. The secondary structure by STRIDE was calculated for the averaged structure. The β-strand order parameter, the averaged β-strand B-factor from the β-strand RMSF, and the β-sheet content based on the intermolecular backbone H-bonds are calculated for the N-terminal (blue area) and C-terminal (green area) β-strands separately as a function of peptide number. Peaks in the Sβ-strand and percent of β-sheet content curves indicate a well-ordered β-strand, whereas troughs in the β-strands B-factor curves denote the ordered β-strand.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2908347&req=5

fig5: Parameters to define the subunits for the 20-mer p3 (Aβ17−42) channel: (a) mapping of x, y coordinates of the β-strands of each peptide onto the x−y plane, (b) the description of secondary structure by STRIDE,(49) (c) the β-strand order parameter Sβ-strand, (d) the averaged β-strand B-factor, and (e) percent of β-sheet content. In the β-strands mapping, the contour lines enclose the high-frequency regions in the order of red < orange < yellow < green < blue. The secondary structure by STRIDE was calculated for the averaged structure. The β-strand order parameter, the averaged β-strand B-factor from the β-strand RMSF, and the β-sheet content based on the intermolecular backbone H-bonds are calculated for the N-terminal (blue area) and C-terminal (green area) β-strands separately as a function of peptide number. Peaks in the Sβ-strand and percent of β-sheet content curves indicate a well-ordered β-strand, whereas troughs in the β-strands B-factor curves denote the ordered β-strand.

Mentions: The p3 channels gradually relax during the simulations. For the small and intermediate p3 channels, as the simulations progress, the inner β-sheet that is initially circular breaks into several small pieces. This inner β-sheet optimization induces β-sheet formation at the outer rim, leading to the observed “subunits”. In the 36-mer channel with smaller curvature, an outer β-sheet was initially present; however, the β-sheet optimization still favors subunit formation. The discontinuous β-sheet network can determine the boundary between the ordered subunits in the channels. Here, the ordered subunits are defined by several criteria: mapping of x, y coordinates of the β-strands of each peptide onto the x−y plane (Figure 5a); description of secondary structure by STRIDE(49) (Figure 5b); “straightness” of the strands by the β-strand order parameters using Sβ = (1/Nv) ∑k = 1Nv((3 cos 2 θα − 1)/2), where θα is the angle between the positional vectors connecting two Cα atoms and Nv is the total number of vector pairs (Figure 5c); the averaged β-strand B-factor or temperature factor is calculated from the rms fluctuations(50) relative to the starting point during the simulations with a simple correlation of B = 8π2(⟨RMSF2⟩/3) (Figure 5d); and the percent of β-sheet content is based on the intermolecular backbone H-bonds between β-strands (Figure 5e). β-Strand mapping reveals the heterogeneous channel shapes, where the 20-mer p3 channel exhibits a pentagonal shape. In the subunits, the β-strands retain the β-sheet secondary structure with a large value of Sβ and a small value of the β-strand B-factor.


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)

Parameters to define the subunits for the 20-mer p3 (Aβ17−42) channel: (a) mapping of x, y coordinates of the β-strands of each peptide onto the x−y plane, (b) the description of secondary structure by STRIDE,(49) (c) the β-strand order parameter Sβ-strand, (d) the averaged β-strand B-factor, and (e) percent of β-sheet content. In the β-strands mapping, the contour lines enclose the high-frequency regions in the order of red < orange < yellow < green < blue. The secondary structure by STRIDE was calculated for the averaged structure. The β-strand order parameter, the averaged β-strand B-factor from the β-strand RMSF, and the β-sheet content based on the intermolecular backbone H-bonds are calculated for the N-terminal (blue area) and C-terminal (green area) β-strands separately as a function of peptide number. Peaks in the Sβ-strand and percent of β-sheet content curves indicate a well-ordered β-strand, whereas troughs in the β-strands B-factor curves denote the ordered β-strand.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5: Parameters to define the subunits for the 20-mer p3 (Aβ17−42) channel: (a) mapping of x, y coordinates of the β-strands of each peptide onto the x−y plane, (b) the description of secondary structure by STRIDE,(49) (c) the β-strand order parameter Sβ-strand, (d) the averaged β-strand B-factor, and (e) percent of β-sheet content. In the β-strands mapping, the contour lines enclose the high-frequency regions in the order of red < orange < yellow < green < blue. The secondary structure by STRIDE was calculated for the averaged structure. The β-strand order parameter, the averaged β-strand B-factor from the β-strand RMSF, and the β-sheet content based on the intermolecular backbone H-bonds are calculated for the N-terminal (blue area) and C-terminal (green area) β-strands separately as a function of peptide number. Peaks in the Sβ-strand and percent of β-sheet content curves indicate a well-ordered β-strand, whereas troughs in the β-strands B-factor curves denote the ordered β-strand.
Mentions: The p3 channels gradually relax during the simulations. For the small and intermediate p3 channels, as the simulations progress, the inner β-sheet that is initially circular breaks into several small pieces. This inner β-sheet optimization induces β-sheet formation at the outer rim, leading to the observed “subunits”. In the 36-mer channel with smaller curvature, an outer β-sheet was initially present; however, the β-sheet optimization still favors subunit formation. The discontinuous β-sheet network can determine the boundary between the ordered subunits in the channels. Here, the ordered subunits are defined by several criteria: mapping of x, y coordinates of the β-strands of each peptide onto the x−y plane (Figure 5a); description of secondary structure by STRIDE(49) (Figure 5b); “straightness” of the strands by the β-strand order parameters using Sβ = (1/Nv) ∑k = 1Nv((3 cos 2 θα − 1)/2), where θα is the angle between the positional vectors connecting two Cα atoms and Nv is the total number of vector pairs (Figure 5c); the averaged β-strand B-factor or temperature factor is calculated from the rms fluctuations(50) relative to the starting point during the simulations with a simple correlation of B = 8π2(⟨RMSF2⟩/3) (Figure 5d); and the percent of β-sheet content is based on the intermolecular backbone H-bonds between β-strands (Figure 5e). β-Strand mapping reveals the heterogeneous channel shapes, where the 20-mer p3 channel exhibits a pentagonal shape. In the subunits, the β-strands retain the β-sheet secondary structure with a large value of Sβ and a small value of the β-strand B-factor.

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