title: Homogeneous and heterogeneous tertiary structure ensembles of amyloid-β peptides.
abstract: The interplay of modern molecular simulation and high-quality nuclear magnetic resonance (NMR) experiments has reached a fruitful stage for quantitative characterization of structural ensembles of disordered peptides. Amyloid-β 1-42 (Aβ42), the primary peptide associated with Alzheimer's disease, and fragments such as Aβ21-30 are both classified as intrinsically disordered peptides (IDPs). We use a variety of NMR observables to validate de novo molecular dynamics simulations in explicit water to characterize the tertiary structure ensemble of Aβ42 and Aβ21-30 from the perspective of their classification as IDPs. Unlike the Aβ21-30 fragment that conforms to expectations of an IDP that is primarily extended, we find that Aβ42 samples conformations reflecting all possible secondary structure categories and spans the range of IDP classifications from collapsed structured states to highly extended conformations, making it an IDP with a far more heterogeneous tertiary ensemble.
authors.affiliation: Graduate Group in Biophysics, University of California, Berkeley, California 94720, United States.
authors.forename: K Aurelia
authors.initials: KA
authors.lastname: Ball
authors.forename: Aaron H
authors.initials: AH
authors.lastname: Phillips
authors.forename: Paul S
authors.initials: PS
authors.lastname: Nerenberg
authors.forename: Nicolas L
authors.initials: NL
authors.lastname: Fawzi
authors.forename: David E
authors.initials: DE
authors.lastname: Wemmer
authors.forename: Teresa
authors.initials: T
authors.lastname: Head-Gordon
mesh_terms: D020816:Amino Acid Motifs; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000145:classification; D006801:Humans; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000737:chemistry* / Q000145:classification; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C501831:amyloid beta-protein (21-30)