title: Zinc ions promote Alzheimer Abeta aggregation via population shift of polymorphic states.
abstract: Although a key factor in Alzheimer's disease etiology is enrichment of Zn(2+) in aggregates, and there are data suggesting that zinc promotes aggregation, how Zn(2+)-Abeta coordination promotes aggregation is elusive. Here we probe the structures and mechanisms through which Zn(2+) can affect amyloidosis. By covalently linking fragments (that have experiment-based coordinates) we observed that, in oligomeric Zn(2+)-Abeta(42), Zn(2+) can simultaneously coordinate intra- and intermolecularly, bridging two peptides. Zinc coordination significantly decreases the solvation energy for large Zn(2+)-Abeta(42) oligomers and thus enhances their aggregation tendency. Zn(2+) binding does not change the beta-sheet association around the C-terminal hydrophobic region; however, it shifts the relative population of the preexisting amyloid polymorphic ensembles. As a result, although a parallel beta-sheet arrangement is still preferred, antiparallel and other less structured assemblies are stabilized, also becoming major species. Overall, Zn(2+) coordination promotes Abeta(42) aggregation leading to less uniform structures. Our replica exchange molecular dynamics simulations further reproduced an experimental observation that the increasing Zn(2+) concentration could slow down the aggregation rate, even though the aggregation rates are still much higher than in Zn(2+)-free solution.
authors.affiliation: Center for Cancer Research Nanobiology Program, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Miller
authors.forename: Buyong
authors.initials: B
authors.lastname: Ma
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D002413:Cations, Divalent / Q000737:chemistry; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry*; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D012995:Solubility; D015032:Zinc / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D002413:Cations, Divalent; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D015032:Zinc
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