Computational Study on the Assembly of Amyloid ß-Peptides in the Hydrophobic Environment.

Fibrillated aggregation of amyloid ß (Aß) peptides is a potential factor causing toxic amyloid deposition in neurodegenerative diseases. A toxic fibril formation of Aß is known to be enhanced on the ganglioside-rich lipid membrane containing some amounts of cholesterol and sphingomyelin. This ganglioside-rich membrane is supposed to provide a hydrophobic environment that promotes the formation of Aß fibrils. Molecular dynamics simulations were carried out to investigate the structure of Aß complex in the hydrophobic solution composed of dioxane and water molecules. The Aß conformation was contrasted to that in the aqueous condition by executing multiple computational trials with the calculation models containing one, four, or six Aß peptides. The conformation was also compared between the calculations with the 42-mer (Aß42) and 40-mer (Aß40) peptides. The simulations for Aß42 demonstrated that Aß peptides had a tendency to stretch out in the hydrophobic environment. In contrast, Aß peptides were closely packed in the aqueous solution, and the motions of Aß peptides were suppressed significantly. The N-terminal polar domains of Aß peptides tended to be positioned at the inside of the Aß complex in the hydrophobic environment, which supported the C-terminal domains in expanding outward for inter-molecular interaction. Since Aß peptides were not tightly packed in the hydrophobic environment, the total surface area of the Aß complex in the hydrophobic solution was larger than that in the aqueous one. The simulation for Aß40 peptides also showed a difference between the hydrophobic and aqueous solutions. The difference was compatible with the results of Aß42 in the structure of the Aß complex, while the C-terminal outward expansion was not so distinct as Aß42 peptides.