Inhibition of Fibril Formation by Tyrosine Modification of Diphenylalanine: Crystallographic Insights

The self-assemblies of diphenylalanine
and its tyrosine analogues
have been investigated. The peptide Boc-Phe-Phe-OMe (1), having a sequence identity with the central hydrophobic cluster
(CHC) of Alzheimer’s β-amyloid diphenylalanine motif,
self-assembles to produce twisted fibrils. In contrast, the tyrosine-modified
analogues Boc-Phe-Tyr-OMe (2), Boc-Tyr-Phe-OMe (3), and Boc-Tyr-Tyr-OMe (4), self-assemble to
form microspheres. The X-ray crystallography reveal that the peptide 1 adopts an inverse γ-turn structure and self-associates
as a hydrogen-bonded chain of molecules along a 2-fold screw axis,
whereas the tyrosine-modified analogues exhibit parallel β-sheet
aggregation and cyclic packing in higher-order assembly. The structural
analysis of the peptides as described here can serve as a basis for
de novo design and therapeutics.