Is Supramolecular Filament Chirality the Underlying Cause of Major Morphology Differences in Amyloid Fibrils?

Abstract

The unique enhanced sensitivity of vibrational circular dichroism (VCD) to the formation and development of amyloid fibrils in solution is extended to four additional fibril-forming proteins or peptides where it is shown that the sign of the fibril VCD pattern correlates with the sense of supramolecular filament chirality and, without exception, to the dominant fibril morphology as observed in AFM or SEM images. Previously for insulin, it has been demonstrated that the sign of the VCD band pattern from filament chirality can be controlled by adjusting the pH of the incubating solution, above pH 2 for “normal” left-hand-helical filaments and below pH 2 for “reversed” right-hand-helical filaments. From AFM or SEM images, left-helical filaments form multifilament braids of left-twisted fibrils while the right-helical filaments form parallel filament rows of fibrils with a flat tape-like morphology, the two major classes of fibril morphology that from deep UV resonance Raman scattering exhibit the same cross-β-core secondary structure. Here we investigate whether fibril supramolecular chirality is the underlying cause of the major morphology differences in all amyloid fibrils by showing that the morphology (twisted versus flat) of fibrils of lysozyme, apo-α-lactalbumin, HET-s (218–289) prion, and a short polypeptide fragment of transthyretin, TTR (105–115), directly correlates to their supramolecular chirality as revealed by VCD. The result is strong evidence that the chiral supramolecular organization of filaments is the principal underlying cause of the morphological heterogeneity of amyloid fibrils. Because fibril morphology is linked to cell toxicity, the chirality of amyloid aggregates should be explored in the widely used in vitro models of amyloid-associated diseases.

Rapid Filament Supramolecular Chirality Reversal of HET-s (218–289) Prion Fibrils Driven by pH Elevation

“…[4][5][6]13,14 One can suspect that pH-driven unwinding of left-twisted HET-s (218−289) prion fibrils might cause significant changes in their supramolecular chirality. This is confirmed by VCD observations.…”

Studying the stereostructures of biomolecules and their analogs by vibrational circular dichroism

“…34 Although the origin of this enhanced fibril VCD signal is not fully understood, VCD spectroscopy has been able to distinguish macroscopically different fibril supramolecular structures. 35,36 Figure 5b shows the IR and VCD spectra of a glycopeptide with antifreeze activity (5a) measured in H 2 O. The disaccharide attached to threonine is essential for the formation of its left-handed polyproline type II helix secondary structure as well as its antifreeze activity.…”

Molecular-level insights of early-stage prion protein aggregation on mica and gold surface determined by AFM imaging and molecular simulation

“…[9][10][11] And compared with these traditional technologies, the atomic force microscopy (AFM) provides additional information on 3D morphology structures and conformation evolution of PrP aggregates with time. [12][13][14] But most AFM-based studies focused on imaging the microfibers or large aggregations in extreme conditions which are far from the physiological environment of human bodies, such as in high concentrations [15], after long-time incubation [16], and at high…”