(274b) Conformational Landscape of Amyloidal Polypeptides

One of the hallmarks of neurodegenerative diseases is amyloid fibril deposits. These are large, structured β-sheet aggregates that are insoluble and thermodynamically very stable. Amyloid formation begins with the assembly of often unfolded or misfolded relatively short polypeptide segments. The propensity of a polypeptide chain to aggregate into amyloids is dependent on several factors including charge, sequence, and hydrophobicity. The secondary structure of the polypeptide segment also plays an important role, and many amyloidal polypeptides have been found to originate from misfolded a-helical structures. It is widely believed that amyloid aggregates initiate from locally unfolded secondary structures. It has been recently suggested that these unfolded states are accessible under physiological conditions, for example, via thermal fluctuations. We performed extensive analysis on protein datasets and found that polypeptide sequences classified as amyloidal have geometric signatures that differ from non-amyloidal sequences. With the new geometric interpretation, we map the energy landscape of the polypeptide backbone on the Ramachandran dihedral coordinates and suggest low energy barrier pathways for misfolding from a-helix to β-sheet structures.