Conformational Selection as the Driving Force of Amyloid β Chiral Inactivation

We recently introduced amyloid β chiral inactivation (Aβ-CI) as a molecular approach that uses mirror-image peptides to chaperone the natural Aβ stereoisomer into a less toxic state. The oligomer-to-fibril conversion mechanism remains the subject of active research. Perhaps the most striking feature of Aβ-CI is the virtual obliteration of the incubation/induction phase that is so characteristic of Aβ fibril formation kinetics. This qualitative change is indicative of the distinct mechanistic pathway Aβ-CI operates through. The current working model of Aβ-CI invokes the formation of "rippled" cross-β sheets, in which alternating l- and d-peptide strands form periodic networks. However, the assumption of rippled cross-β sheets does not per se explain the dramatic changes in reaction kinetics upon mixing of Aβ enantiomers. Herein, it is shown by DFT computational methods that the individual peptide strands in rippled cross-β networks are less conformationally strained than their pleated counterparts. This means that the adoption of fibril-seeding conformations is more probable for rippled cross-β. Conformational selection is thus suggested as the mechanistic rationale for the acceleration of fibril formation upon Aβ-CI.