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Structures of soluble amyloid oligomers from computer simulations
Author(s) -
Melquiond Adrien,
Mousseau Normand,
Derreumaux Philippe
Publication year - 2006
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.21100
Subject(s) - fibrillogenesis , fibril , monomer , beta sheet , biophysics , amyloid fibril , amyloid (mycology) , chemistry , multiplicity (mathematics) , crystallography , peptide , biochemistry , biology , polymer , amyloid β , medicine , inorganic chemistry , disease , organic chemistry , pathology , mathematical analysis , mathematics
Alzheimer's, Parkinson's, and Creutzfeldt‐Jakob's neurodegenerative diseases are all linked with the assembly of normally soluble proteins into amyloid fibrils. Because of experimental limitations, structural characterization of the soluble oligomers, which form early in the process of fibrillogenesis and are cytotoxic, remains to be determined. In this article, we study the aggregation paths of seven chains of the shortest amyloid‐forming peptide, using an activitated method and a reduced atomic representation. Our simulations show that disordered KFFE monomers ultimately form three distinct topologies of similar energy: amorphous oligomers, incomplete rings with β‐barrel character, and cross‐β‐sheet structures with the meridional but not the equatorial X‐ray fiber reflections. The simulations also shed light on the pathways from misfolded aggregates to fibrillar‐like structures. They also underline the multiplicity of building blocks that can lead to the formation of the critical nucleus from which rapid growth of the fibril occurs. Proteins 2006. © 2006 Wiley‐Liss, Inc.