Directing the secondary structure of polypeptides at will: from helices to amyloids and back again?

Abstract

An ageing society faces an increasing number of neurodegenerative diseases such as Alzheimer's, Parkinson’s, and Creutzfeld–Jacob disease. The deposition of amyloid fibrils is a pathogenic factor causing the destruction of neuronal tissue. Amyloid-forming proteins are mainly α-helical in their native conformation, but undergo an α-helix to β-strand conversion before or during fibril formation. Partially unfolded or misfolded β-sheet fragments are discussed as direct precursors of amyloids. To potentially cure neurodegenerative diseases we need to understand the complex folding mechanisms that shift the equilibrium from the functional to the pathological isoform of the proteins involved. This paper describes a novel approach that allows us to study the interplay between peptide primary structure and environmental conditions for peptide and protein folding in its whole complexity on a molecular level. This de novo designed peptide system may achieve selective inhibition of fibril formation.