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

Abstract

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.

Simulation Study on Complex Conformations of Aβ₄₂ Peptides on a GM1 Ganglioside-Containing Lipid Membrane

“…The purpose of this study is to clarify the interactions among the multiple Aβ peptides on the lipid membrane. In our previous work, 21) Aβ peptides were included in the calculation model one by one up to three, because the main purpose of the previous work is to examine the Aβ interaction with GM1-containing membrane. In another work that examined the behavior of Aβ on the GM1-containing membrane, 24) the calculation models contained Aβ monomer or dimer.…”

“…The starting molecular geometry was settled by referring to the final structure of our previous MD simulation using a model with three Aβs. 21) Hence, three Aβ 42 peptides were already bound to the membrane surface. Another Aβ 42 peptide, the fourth Aβ labeled as Aβ4, was put into the water layer of the model system.…”

“…22,23) Only a few studies employed the calculation models that included GM1 and Chol in the lipid membrane. 21,24) We have developed a modeling technique and simulation method for mixed membranes. 21,25,26) In experiments, the presence of GM1 ganglioside in a raft-like membrane was * To whom correspondence should be addressed.…”

“…21,24) We have developed a modeling technique and simulation method for mixed membranes. 21,25,26) In experiments, the presence of GM1 ganglioside in a raft-like membrane was * To whom correspondence should be addressed. e-mail: hoshino@chiba-u.jp…”

Ganglioside-magnetosome complex formation enhances uptake of gangliosides by cells

“…[15][16][17] The primary obstacle to the administration of gangliosides to cells is their tendency to aggregate into micelles in aqueous media. In studies by Orlando et al 18 and Ghidoni et al 19 , only 1%-3% of administered GM 1 actually entered brain cells in mouse and rat models.…”