Structural Convergence Among Diverse, Toxic β-Sheet Ion Channels

• Published in: The journal of physical chemistry. B 2010-07, Vol.114 (29), p.9445-9451
• Main Authors: Jang, Hyunbum, Teran Arce, Fernando, Ramachandran, Srinivasan, Capone, Ricardo, Lal, Ratnesh, Nussinov, Ruth
• Format: Article
• Language: English
• Subjects: Amyloid beta-Peptides - chemistry; Antimicrobial Cationic Peptides - chemistry; B: Macromolecules, Soft Matter; Ion Channels - chemistry; Lipid Bilayers - chemistry; Microscopy, Atomic Force; Molecular Dynamics Simulation; Peptides - chemistry; Protein Structure, Secondary
• ISSN: 1520-6106; 1520-5207; 1520-5207
• DOI: 10.1021/jp104073k

Recent studies show that an array of β-sheet peptides, including N-terminally truncated Aβ peptides (Aβ11−42/17−42), K3 (a β2-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, β-strand-turn-β-strand coordinates, we modeled truncated Aβ 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 Aβ9−42, K3 fragment, and PG-1 channels and highlights the bilayer-supported preferred toxic β-channel sizes and organization, regardless of the peptide sequence.