Computational assembly of polymorphic amyloid fibrils reveals stable aggregates

Abstract

Amyloid proteins aggregate into polymorphic fibrils that damage tissues of the brain, nerves, and heart. Experimental and computational studies have examined the structural basis and the nucleation of short fibrils, but the ability to predict and precisely quantify the stability of larger aggregates has remained elusive. We established a complete classification of fibril shapes and developed a tool called CreateFibril to build such complex, polymorphic, modular structures automatically. We applied stability landscapes, a technique we developed to reveal reliable fibril structural parameters, to assess fibril stability. CreateFibril constructed HET-s, Aβ, and amylin fibrils up to 17 nm in length, and utilized a novel dipolar solvent model that captured the effect of dipole-dipole interactions between water and very large molecular systems to assess their aqueous stability. Our results validate experimental data for HET-s and Aβ, and suggest novel (to our knowledge) findings for amylin. In particular, we predicted the correct structural parameters (rotation angles, packing distances, hydrogen bond lengths, and helical pitches) for the one and three predominant HET-s protofilaments. We reveal and structurally characterize all known Aβ polymorphic fibrils, including structures recently classified as wrapped fibrils. Finally, we elucidate the predominant amylin fibrils and assert that native amylin is more stable than its amyloid form. CreateFibril and a database of all stable polymorphic fibril models we tested, along with their structural energy landscapes, are available at http://amyloid.cs.mcgill.ca.

Figure 1

Classification of the polymorphic fibril structures produced by CreateFibril. Ring fibrils pack and join at turns, Polygon fibrils join to create a polygon-shaped core, and Stack fibrils pack laterally.

Figure 2

Different parameters used by CreateFibril to build structures. The parameters drawn are the fibril axis location and direction, rotation angle of amyloid monomers along the fibril axis, H-bond distance of β-sheets along the fibril axis, and PD of filaments perpendicular to the fibril axis. Parameters not drawn include the protein PDB structure file, fibril class type, and length of fibril.

Figure 3

HET-s Single fibril parameter findings. (a) Heatmap representation of the stability landscape of Single HET-s structures, exploring the rotational angle θ (y axis) and β-sheet bonding distance d (x axis). Green circles indicate stable structures with low enthalpy drift, red circles indicate unstable structures with high enthalpy drift, and black circles are intermediately stable structures. (b) Single HET-s fibril built by CreateFibril with the values of θ = 22° and d = 4.7 Å taken from the best result in panel a enclosed by the red square. (c) Stability landscape of the PD of HET-s 3-Polygon. Energy values are in kJ/mol.

Figure 4

Cross-sectional view of the hydration-shell effect on the hydrophobicity of the predominant HET-s, Aβ, and amylin fibrils produced by AQUASOL. Blue regions represent hydrophilic residues and red regions represent hydrophobic residues. (a and b) HET-s Single fibrils possess a hydrophobic core around which they aggregate (a), and the branching residues of the Single fibrils help hide hydrophobic residues of their neighboring fibril when packed in the 3-Ring structure (b). (d and e) Aβ 2-Stack and 3-Polygon fibrils aggregate, creating a hydrophobic core. (f and g) The native amylin contains many hydrophobic residues (f) but possesses a lower energy than its amyloid counterpart (g). (h) To hide their hydrophobic residues, amylin amyloids aggregate in the 2-Stack polymorph.

Figure 5

Energies of Aβ and amylin fibrils as they aggregate. (a and c) Solvation energy by dipolar solvent. (b and d) Free energy by dipolar solvent.

Figure 6

Aβ wrapped fibrils. (a and b) Cross-sectional top view (a) and side view (b) of the wrapped Aβ fibril. (c) Heatmap representation of the stability landscape of Aβ wrapped fibrils characterized by rotational angle θ (y axis) and crossing angle ω (x axis). Green circles indicate stable structures with low energy, red circles indicate unstable structures with high energy, and black circles are intermediately stable structures. Energy values are in kJ/mol. (d) The 2-StackWrap_A structure with a crossing angle of 8° and rotation angle of −3° is more stable than a nonwrapped 2-Stack structure. 2-StackWrap_B has a crossing angle of 59° and rotation angle of −11°.