Elucidating structure

We anticipate that these studies will pave the way for developing diagnostics and therapeutics to combat Alzheimer’s disease, Parkinson’s disease, and other amyloid diseases Chapter 2 presents the X-ray crystallographic structures of oligomers formed by a 20-residue peptide segment derived from Aβ.

The development of a peptide, in which Aβ17–36 is stabilized as a β-hairpin is described and the X-ray crystallographic structures of oligomers it forms are reported.

An N-methyl group is installed on one of the β-strands to prevent uncontrolled aggregation.

These design features facilitate crystallization of the β-hairpin mimics and determination of the X-ray crystallographic structures of the oligomers that they form.

This hierarchical assembly provides a model, in which full-length Aβ transitions from an unfolded monomer to a folded β-hairpin, which assembles to form oligomers that further pack to form an annular pore.

This model may provide a better understanding of the molecular basis of Alzheimer’s disease at atomic resolution.

While this problem is acutely relevant in donor-acceptor blends for photovoltaic applications where the bulk heterojunction morphology is well-known to play a critical role in device performance, charge transport through crystalline-amorphous microstructures and in semiconductor-insulator blends for flexible transistors share similar physical characteristics.

In this presentation, we will introduce a unique approach to developing structure-property relationships for charge transport in these systems using kinetic Monte Carlo simulations with material morphologies derived from spectroscopic transmission electron microscope tomography.

The first glimpses of the chemical basis of Alzheimer’s disease began with the identification of “amyloid” plaques in the brain in 1892 and extended to the identification of proteinaceous fibrils with “cross-β” structure in 1968.

Further efforts led to the discovery of the β-amyloid peptide Aβ as a 40- or 42-amino acid peptide that is responsible for the plaques and fibrils.

At this point, a three-decade long marathon began to elucidate the structure of the fibrils and identify the molecular basis of Alzheimer’s disease.

Our studies have revealed a previously undiscovered mode of self-assembly, whereby three Aβ β-hairpin mimics assemble to form a triangular trimer.

The triangular trimers are remarkable, because they contain two largely hydrophobic surfaces that pack together with other triangular trimers to form higher-order oligomers, such as hexamers and dodecamers.

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