title: Helix-dipole effects in peptide self-assembly to amyloid.
abstract: The formation of amyloid fibrils is associated with incurable diseases including Alzheimer's, Parkinson's, and type 2 diabetes. Important mechanistic details of the self-assembly are unknown partly because of the absence of a clear structural characterization of intermediates. There is experimental evidence, however, for α-helical intermediates that has come primarily from circular dichroism spectroscopy. Here, we strengthen the evidence for helical intermediates by demonstrating helix-dipole effects in the early events of self-assembly. Previously, we showed that capped peptides containing the part of the islet amyloid polypeptide that may be responsible for the initial intermolecular contacts (Acetyl-R(11)LANFLVHSSNNFGA(25)-NH(2) and Acetyl-R(11)LANFLVHSGNNFGA(25)-NH(2) which contains the S20G mutation associated with early onset type 2 diabetes) self-assemble via helical intermediates [Liu et al. (2010) J. Am. Chem. Soc.132, 18223-18232]. We demonstrate here that when the peptides are uncapped, they do not self-assemble as indicated primarily by circular dichroism and nuclear magnetic resonance data. Self-assembly is restored when the charge on α-NH(3)(+) of Arg11 is eliminated but not when the charge on α-COO(-) of Ala25 is removed, consistent with the helicity of the peptides skewed toward the N-terminus. Our results strengthen the hypothesis that α-helical intermediates are on pathway to amyloid formation and indicate that the helix dipole is an attractive target for inhibiting the formation of α-helical assemblies.
authors.affiliation: Carlson School of Chemistry and Biochemistry, Clark University, 950 Main Street, Worcester, MA 01610, USA.
authors.forename: Gai
authors.initials: G
authors.lastname: Liu
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Robbins
authors.forename: Samuel
authors.initials: S
authors.lastname: Sparks
authors.forename: Veli
authors.initials: V
authors.lastname: Selmani
authors.forename: Kalin M
authors.initials: KM
authors.lastname: Bilides
authors.forename: Erin E
authors.initials: EE
authors.lastname: Gomes
authors.forename: Noel D
authors.initials: ND
authors.lastname: Lazo
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics; D002942:Circular Dichroism; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments