title: Understanding Amyloid-β Oligomerization at the Molecular Level: The Role of the Fibril Surface.
abstract: The aggregation of the amyloid β-peptide into fibrils is a complex process that involves mechanisms such as primary and secondary nucleation, fibril elongation and fibril fragmentation. Some of these processes generate neurotoxic Aβ oligomers, which are involved in the development of Alzheimer's disease. Recent experimental studies have emphasized the role of the fibril as a catalytic surface for the production of highly toxic oligomers during secondary nucleation. By using molecular dynamics simulations, we show that it is the hydrophobic fibril region that causes the structural changes required for catalyzing the formation of β-sheet-rich Aβ1-42 oligomers on the fibril surface. These results reveal, for the first time, the molecular basis of the secondary nucleation pathway.
authors.affiliation: Institute of Complex Systems: Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Barz
authors.affiliation: Institute of Theoretical and Computational Chemistry, Heinrich Heine University Düsseldorf, Universitätstrasse 1, 40225, Düsseldorf, Germany. b.strodel@fz-juelich.de, b.barz@fz-juelich.de.|Institute of Complex Systems: Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH, 52425, Jülich, Germany. b.strodel@fz-juelich.de, b.barz@fz-juelich.de.
authors.forename: Birgit
authors.identifier: http://orcid.org/0000-0002-8734-7765
authors.initials: B
authors.lastname: Strodel
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D013499:Surface Properties
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; aggregation; amyloid β-peptides; molecular dynamics; secondary nucleation