Using chirality to probe the conformational dynamics and assembly of intrinsically disordered amyloid proteins.

Intrinsically disordered protein (IDP) conformers occupy large regions of conformational space and display relatively flat energy surfaces. Amyloid-forming IDPs, unlike natively folded proteins, have folding trajectories that frequently involve movements up shallow energy gradients prior to the "downhill" folding leading to fibril formation. We suggest that structural perturbations caused by chiral inversions of amino acid side-chains may be especially valuable in elucidating these pathways of IDP folding. Chiral inversions are subtle in that they do not change side-chain size, flexibility, hydropathy, charge, or polarizability. They allow focus to be placed solely on the question of how changes in amino acid side-chain orientation, and the resultant alterations in peptide backbone structure, affect a peptide's conformational landscape (Ramachandran space). If specific inversions affect folding and assembly, then the sites involved likely are important in mediating these processes. We suggest here a "focused chiral mutant library" approach for the unbiased study of amyloid-forming IDPs.