Conformational Selection as the Driving Force of Amyloid β Chiral Inactivation

Abstract

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 land 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.

Defining the Landscape of the Pauling-Corey Rippled Sheet: An Orphaned Motif Finding New Homes

“…One of those structures was found to be more stable than LVFFA:LVFFA homochiral dimers from three published Aβ fibril structures. 66 Since then, Raskatov found a rippled antiparallel cross-β LVFFA:lvffa dimer that is even more stable ( Figure 13 ). Energetics may be different for more extended sheets.…”

“… 68 The antiparallel structures were built from Pauling-Corey coordinates, and all four structures were N-terminally acetylated and C-terminally amidated, and fully geometry-optimized as described previously. 63 , 66 , 67 , 69 …”

“…Once a competent nucleus is formed, elongation should be energetically downhill, most likely characterized by monomer addition, 75 or even preformed segments to the growing fibril with the complicating factors of strand registry, direction (parallel vs antiparallel), and mirror-image pairing. 76 In addition, conformational selection has recently been proposed to accelerate fibril formation upon enantiomer mixing; 66 future research may reveal other underlying reasons for this fascinating effect.…”

A DFT study of structure and stability of pleated and rippled cross‐β sheets with hydrophobic sidechains

“…DFT-based work found the rippled parallel LVFFA dimer to be favored over three distinct, experimentally observed pleated frameworks. [15] The rippled cross-β topography has thus burgeoned as a valuable design principle for materials and in biomedical applications. The purpose of this DFT study was to determine the relative impact of steric bulk in pleated and rippled cross-β model systems by considering certain hydrophobic amino acid side chains.…”

Autofluorescence of Amyloids Determined by Enantiomeric Composition of Peptides

“…These observations are in agreement with reported density functional theory simulations, explaining that the formation of racemic rippled β-sheet fibrils is energetically more favorable than that of enantiomerically pure pleated ones. 35 , 36 Moreover, the recently accelerated fibrillation process upon mixing of mirror-image peptides was reported. 37 This also explains why spontaneous resolution from the D/L mixture into enantiopure amyloid fibrils is unfavorable.…”