Binding and Aggregation Mechanism of Amyloid β‑Peptides onto the GM1 Ganglioside-Containing Lipid Membrane

• Published in: The journal of physical chemistry. B Vol. 117; no. 27; pp. 8085 - 8094
• Main Authors: Hoshino, Tyuji, Mahmood, Md. Iqbal, Mori, Kenichi, Matsuzaki, Katsumi
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 11.07.2013
• Subjects: Agglomeration; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Binding; Biological and medical sciences; Computer simulation; Contact; Fundamental and applied biological sciences. Psychology; G(M1) Ganglioside - chemistry; G(M1) Ganglioside - metabolism; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Lipid Bilayers - chemistry; Lipid Bilayers - metabolism; Lipids; Mathematical models; Membranes; Molecular biophysics; Molecular Dynamics Simulation; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptides; Protein Binding; Protein Structure, Secondary; Fluctuations; Amyloid; Ganglioside; Adhesion; Molecular cluster; Molecular dynamics method
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/jp4029062

Accumulation and fibril formation of amyloid β (Aβ) peptides onto a ganglioside-rich lipid membrane is a cause of neuro-disturbance diseases. To find out a measure for suppressing the nucleation of a seed for amyloid fibrils, the mechanism of the initial binding of Aβ to the membrane should be clarified. Molecular dynamics simulations were carried out to investigate the adhesion process of Aβ peptides onto a GM1-ganglioside-containing membrane. Multiple computational trials were executed to analyze the probability of occurrence of Aβ binding by using calculation models containing a mixed lipid membrane, water layer, and one, two, or three Aβs. The simulations demonstrated that Aβ peptides approached the membrane after fluctuation in the water layer and occasionally made steady contact with the membrane. Once the steady contact had been established, Aβ was unlikely to be detached from the membrane and developed into a more stably bound form. In the stably bound form, neuraminic acids on the GM1 cluster strongly held the side chain of Lys28 of Aβ, which caused deformation of the C-terminal region of the Aβ. Since the C-terminal region of the Aβ peptide contains many hydrophobic residues, its deformation on the membrane enhances the hydrophobic interaction with other Aβ peptides. The contact region of two Aβs evolved into a parallel β-sheet form, and the third Aβ was observed to be bound to the complex of two Aβs to make a bundle of Aβ peptides. Some key structures involved in the Aβ aggregation on the GM1-containing membrane were deduced from the multiple simulations.