Folding and membrane insertion of amyloid-beta (25-35) peptide and its mutants: Implications for aggregation and neurotoxicity

• Published in: Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2010-06, Vol.78 (8), p.1909-1925
• Main Authors: Tsai, Hui-Hsu Gavin, Lee, Jian-Bin, Tseng, Sheng-Shiuan, Pan, Xiao-An, Shih, Yuan-Ci
• Format: Article
• Language: English
• Subjects: aggregation; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - toxicity; amyloid-beta; Cell Membrane - drug effects; Cell Membrane - metabolism; Humans; interfacial folding; Magnetic Resonance Spectroscopy; membrane insertion; Models, Molecular; Mutant Proteins - chemistry; Mutant Proteins - metabolism; Mutant Proteins - toxicity; neurotoxicity; Neurotoxins - chemistry; Neurotoxins - metabolism; Neurotoxins - toxicity; Peptides - chemistry; Peptides - metabolism; Peptides - toxicity; Protein Folding - drug effects; Protein Structure, Quaternary; Protein Structure, Secondary; Protons; replica-exchange molecular dynamics; Water - chemistry
• ISSN: 0887-3585; 1097-0134
• DOI: 10.1002/prot.22705

The mechanisms of interfacial folding and membrane insertion of the Alzheimer's amyloid‐β fragment Aβ(25–35) and its less toxic mutant, N27A‐Aβ(25–35) and more toxic mutant, M35A‐Aβ(25–35), are investigated using replica–exchange molecular dynamics in an implicit water‐membrane environment. This study simulates the processes of interfacial folding and membrane insertion in a spontaneous fashion to identify their general mechanisms. Aβ(25–35) and N27A‐Aβ(25–35) peptides share similar mechanisms: the peptides are first located in the membrane hydrophilic region where their C‐terminal residues form helical structures. The peptides attempt to insert themselves into the membrane hydrophobic region using the C‐terminal or central hydrophobic residues. A small portion of peptides can successfully enter the membrane's hydrophobic core, led by their C‐terminal residues, through the formation of continuous helical structures. No detectable amount of M35A‐Aβ(25–35) peptides appeared to enter the membrane's hydrophobic core. The three studied peptides share a similar helical structure for their C‐terminal five residues, and these residues mainly buried within the membrane's hydrophobic region. In contrast, their N‐terminal properties are markedly different. With respect to the Aβ(25–35), the N27A‐Aβ(25–35) forms a more structured helix and is buried deeper within the membrane, which may result in a lower degree of aggregation and a lower neurotoxicity; in contrast, the less structured and more water‐exposed M35A‐Aβ(25–35) is prone to aggregation and has a higher neurotoxicity. Understanding the mechanisms of Aβ peptide interfacial folding and membrane insertion will provide new insights into the mechanisms of neurodegradation and may give structure‐based clues for rational drug design preventing amyloid associated diseases. Proteins 2010. © 2010 Wiley‐Liss, Inc.