Queuing up: Molecular orientation within macroscopically aligned nanotubes of the peptide AAAAAAK can be studied by solid‐state NMR and IR spectroscopy. Line shape analysis of the NMR spectra indicates that the peptide NH bonds are tilted 65–70° relative to the nanotube long axis. Re‐evaluation of earlier X‐ray fiber diffraction data suggests that the peptide molecules are hydrogen‐bonded in a helical arrangement along the nanotube axis.

The amyloid plaques associated with Alzheimer's disease (AD) comprise fibrillar amyloid-β (Aβ) peptides as well as non-protein factors including glycosaminoglycan (GAG) polysaccharides. GAGs affect the kinetics and pathway of Aβ self-assembly and can impede fibril clearance and therefore may be accessory molecules in AD. Here we describe an investiga-tion of GAG-Aβ fibril interactions and report the first high-resolution details from the perspective of the saccharide. Binding analysis indicated that the GAG proxy heparin has a re-markably high specificity for Aβ fibrils with 3-fold cross-sectional symmetry (3Q). Chemical synthesis of a uniformly ¹³C-labeled octasaccharide heparin analog enabled magic-angle spinning solid-state NMR (SSNMR) of the GAG bound to the fibrils, and measurements of dynamics reveal a tight complex in which all saccharide residues are restrained with-out undergoing substantial conformational changes. Intramo-lecular ¹³C-¹⁵N dipolar dephasing is consistent with close (< 5 Å) contact between GAG anomeric position(s) and one or more histidine residues in the fibrils. These data provide a detailed model for the interaction between Aβ40 fibrils with 3Q morphology and a major non-protein component of AD plaques, and reveal that GAG-amyloid interactions display a range of affinities that critically depend on the precise details of the fibril architecture.

The aggregation of numerous peptides or proteins has been linked to the onset of disease, including Aβ (amyloid β-peptide) in AD (Alzheimer's disease), asyn (α-synuclein) in Parkinson's disease and amylin in Type 2 diabetes. Diverse amyloidogenic proteins can often be cut down to an SRE (self-recognition element) of as few as five residues that retains the ability to aggregate. SREs can be used as a starting point for aggregation inhibitors. In particular, N-methylated SREs can bind to a target on one side, but have hydrogen-bonding blocked on their methylated face, interfering with further assembly. We applied this strategy to develop Aβ toxicity inhibitors. Our compounds, and a range of compounds from the literature, were compared under the same conditions, using biophysical and toxicity assays. Two N-methylated D-peptide inhibitors with unnatural side chains were the most effective and can reverse Aβ-induced inhibition of LTP (long-term potentiation) at concentrations as low as 10 nM. An SRE in asyn (VAQKTV) was identified using solid-state NMR. When VAQKTV was N-methylated, it was able to disrupt asyn aggregation. N-methylated derivatives of the SRE of amylin are also able to inhibit amylin aggregation.