title: 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.
authors: School of Computer Science, McGill University, Montreal, Canada.
authors: Mohamed Raef
authors: MR
authors: Smaoui
authors: Frédéric
authors: F
authors: Poitevin
authors: Marc
authors: M
authors: Delarue
authors: Patrice
authors: P
authors: Koehl
authors: Henri
authors: H
authors: Orland
authors: Jérôme
authors: J
authors: Waldispühl
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry; D008969:Molecular Sequence Data; D011487:Protein Conformation; D055503:Protein Multimerization; D055550:Protein Stability; D021122:Protein Subunits / Q000737:chemistry; D012984:Software; D014867:Water / Q000737:chemistry
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D021122:Protein Subunits; D014867:Water