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Indexed by:期刊论文

Date of Publication:2014-08-07

Journal:JOURNAL OF PHYSICAL CHEMISTRY B

Included Journals:SCIE、EI、PubMed、Scopus

Volume:118

Issue:31

Page Number:9238-9246

ISSN No.:1520-6106

Abstract:The identification of a secondary nucleation pathway in the early aggregation of amyloid peptides suggests that the generation of toxic oligomers involves both monomers and preformed fibril seeds. To elucidate the underlying molecular mechanism, a set of one-pot coarse-grained molecular dynamics simulations was performed to investigate the self-assembly of amyloid beta peptides in the presence of fibril seeds. It was observed that fibril seeds alone randomly assemble into an elongated protofibril, whereas monomers alone form an elongated globular oligomer with various morphologies. In the mixture of monomers and fibril seeds, both the self-assembly of monomers into small oligomers and the association of monomers and oligomers on the surface of fibril seeds are primarily driven by hydrophobic interactions. The cooperativity of conformational selection and competition leads to different binding propensity of two hydrophobic surfaces of fibril seeds. The molecular architecture of the final aggregate shows that the fibril seeds establish the elongated framework, and oligomers cover them. Oligomers exposed to the solvent are less compact and unstable and can be disassociated from the fibril seeds, providing an origin for oligomers generated from the secondary nucleation pathway.