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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

Potential of mean force (PMF), ΔGPMF, calculated using the equation ΔGPMF = −kBT ln(ρz/ρbulk), where kB is the Boltzmann constant, T is the simulation temperature, ρz is the ion density at the position z along the pore axis, and ρbulk is the ion density in the bulk region, representing the relative free energy profile for Mg2+ (green lines), K+ (red lines), Ca2+ (blue lines), Zn2+ (cyan lines), and Cl− (black lines) as a function of the distance along the pore center axis for the (a) 16-, (b) 20-, and (c) 24-mer p3 (Aβ17−42) channels. The PMF results for the 16- and 20-mers were obtained from the simulations in the zwitterionic DOPC bilayer. The PMF result 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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fig7: Potential of mean force (PMF), ΔGPMF, calculated using the equation ΔGPMF = −kBT ln(ρz/ρbulk), where kB is the Boltzmann constant, T is the simulation temperature, ρz is the ion density at the position z along the pore axis, and ρbulk is the ion density in the bulk region, representing the relative free energy profile for Mg2+ (green lines), K+ (red lines), Ca2+ (blue lines), Zn2+ (cyan lines), and Cl− (black lines) as a function of the distance along the pore center axis for the (a) 16-, (b) 20-, and (c) 24-mer p3 (Aβ17−42) channels. The PMF results for the 16- and 20-mers were obtained from the simulations in the zwitterionic DOPC bilayer. The PMF result for the 24-mer was obtained from the anionic bilayer containing POPC and POPG at a molar ratio of 4:1.

Mentions: Electrophysiological studies showed heterogeneous single channel conductance for truncated Aβ channels.(27) The heterogeneous channel currents suggest that multiple arrangements of oligomeric subunits with various sizes of the inner pore lead to multiple conductances. In previous studies,27,29−31 we suggested that the negatively charged Glu22 side chains serve as cation binding sites, attracting cations into the pore. The ions’ behavior in the pore can be observed through calculations of the potential of mean force (PMF) representing the relative free energy profile for each ion across the bilayer. In addition to the cation binding sites in the pore, cations can also interact with the phosphate headgroups at the lipid/water interface in both bilayer leaflets and the Aβ C-termini. Thus, the radical cation interactions may lead to PMF curves with three minima. In the simulations, the channel systems contain four cations, Mg2+, Ca2+, K+, and Zn2+, at the same concentration (25 mM), and an anion, Cl− (Figure 7).


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)

Potential of mean force (PMF), ΔGPMF, calculated using the equation ΔGPMF = −kBT ln(ρz/ρbulk), where kB is the Boltzmann constant, T is the simulation temperature, ρz is the ion density at the position z along the pore axis, and ρbulk is the ion density in the bulk region, representing the relative free energy profile for Mg2+ (green lines), K+ (red lines), Ca2+ (blue lines), Zn2+ (cyan lines), and Cl− (black lines) as a function of the distance along the pore center axis for the (a) 16-, (b) 20-, and (c) 24-mer p3 (Aβ17−42) channels. The PMF results for the 16- and 20-mers were obtained from the simulations in the zwitterionic DOPC bilayer. The PMF result 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

fig7: Potential of mean force (PMF), ΔGPMF, calculated using the equation ΔGPMF = −kBT ln(ρz/ρbulk), where kB is the Boltzmann constant, T is the simulation temperature, ρz is the ion density at the position z along the pore axis, and ρbulk is the ion density in the bulk region, representing the relative free energy profile for Mg2+ (green lines), K+ (red lines), Ca2+ (blue lines), Zn2+ (cyan lines), and Cl− (black lines) as a function of the distance along the pore center axis for the (a) 16-, (b) 20-, and (c) 24-mer p3 (Aβ17−42) channels. The PMF results for the 16- and 20-mers were obtained from the simulations in the zwitterionic DOPC bilayer. The PMF result for the 24-mer was obtained from the anionic bilayer containing POPC and POPG at a molar ratio of 4:1.
Mentions: Electrophysiological studies showed heterogeneous single channel conductance for truncated Aβ channels.(27) The heterogeneous channel currents suggest that multiple arrangements of oligomeric subunits with various sizes of the inner pore lead to multiple conductances. In previous studies,27,29−31 we suggested that the negatively charged Glu22 side chains serve as cation binding sites, attracting cations into the pore. The ions’ behavior in the pore can be observed through calculations of the potential of mean force (PMF) representing the relative free energy profile for each ion across the bilayer. In addition to the cation binding sites in the pore, cations can also interact with the phosphate headgroups at the lipid/water interface in both bilayer leaflets and the Aβ C-termini. Thus, the radical cation interactions may lead to PMF curves with three minima. In the simulations, the channel systems contain four cations, Mg2+, Ca2+, K+, and Zn2+, at the same concentration (25 mM), and an anion, Cl− (Figure 7).

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