Helix-Dipole Effects in Peptide Self-Assembly to Amyloid

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-R11LANFLVHSSNNFGA25-NH2 and Acetyl-R11LANFLVHSGNNFGA25-NH2 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-NH3 + 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.