In silico study of amyloid -protein folding and oligomerization

Experimental findings suggest that oligomeric forms of the amyloid protein (A ) play a critical role in Alzheimer’s disease. Thus, elucidating their structure and the mechanisms of their formation is critical for developing therapeutic agents. We use discrete molecular dynamics simulations and a four-bead protein model to study oligomerization of two predominant alloforms, A 40 and A 42, at the atomic level. The four-bead model incorporates backbone hydrogen-bond interactions and amino acid-specific interactions mediated through hydrophobic and hydrophilic elements of the side chains. During the simulations we observe monomer folding and aggregation of monomers into oligomers of variable sizes. A 40 forms significantly more dimers than A 42, whereas pentamers are significantly more abundant in A 42 relative to A 40. Structure analysis reveals a turn centered at Gly-37–Gly-38 that is present in a folded A 42 monomer but not in a folded A 40 monomer and is associated with the first contacts that form during monomer folding. Our results suggest that this turn plays an important role in A 42 pentamer formation. A pentamers have a globular structure comprising hydrophobic residues within the pentamer’s core and hydrophilic N-terminal residues at the surface of the pentamer. The N termini of A 40 pentamers are more spatially restricted than A 42 pentamers. A 40 pentamers form a -strand structure involving Ala-2–Phe-4, which is absent in A 42 pentamers. These structural differences imply a different degree of hydrophobic core exposure between pentamers of the two alloforms, with the hydrophobic core of the A 42 pentamer being more exposed and thus more prone to form larger oligomers.