title: Side-chain dynamics reveals transient association of Aβ(1-40) monomers with amyloid fibers.
abstract: Low-lying excited states that correspond to rare conformations or transiently bound species have been hypothesized to play an important role for amyloid nucleation. Despite their hypothesized importance in amyloid formation, transiently occupied states have proved difficult to detect directly. To experimentally characterize these invisible states, we performed a series of Carr-Purcell-Meiboom-Gill (CPMG)-based relaxation dispersion NMR experiments for the amyloidogenic Aβ(1-40) peptide implicated in Alzheimer's disease. Significant relaxation dispersion of the resonances corresponding to the side-chain amides of Q15 and N27 was detected before the onset of aggregation. The resonances corresponding to the peptide backbone did not show detectable relaxation dispersion, suggesting an exchange rate that is not within the practical limit of detection. This finding is consistent with the proposed "dock and lock" mechanism based on molecular dynamics simulations in which the Aβ(1-40) monomer transiently binds to the Aβ(1-40) oligomer by non-native contacts with the side chains before being incorporated into the fiber through native contacts with the peptide backbone.
authors.affiliation: Biophysics and Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.
authors.forename: Janarthanan
authors.initials: J
authors.lastname: Krishnamoorthy
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Brender
authors.forename: Subramanian
authors.initials: S
authors.lastname: Vivekanandan
authors.forename: Nicole
authors.initials: N
authors.lastname: Jahr
authors.forename: Ayyalusamy
authors.initials: A
authors.lastname: Ramamoorthy
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)