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

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