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.本研究对二苯丙氨酸及其酪氨酸类似物的自组装行为展开了探究。肽Boc-Phe-Phe-OMe（1）与阿尔茨海默病β-淀粉样蛋白二苯丙氨酸基序的中心疏水簇（CHC）具有序列同源性，其自组装可形成扭曲原纤维。与之相反，经酪氨酸修饰的类似物Boc-Phe-Tyr-OMe（2）、Boc-Tyr-Phe-OMe（3）以及Boc-Tyr-Tyr-OMe（4）则自组装形成微球。X射线晶体学分析表明，肽1采用反向γ转角结构，并沿二重螺旋轴以分子氢键链的形式自缔合；而经酪氨酸修饰的类似物则呈现平行β片层聚集，并在高阶组装中形成环状排布。本研究中针对这些肽的结构分析，可为肽的从头设计与治疗应用提供理论基础。