Qiao Yuchen, Zia Ayisha, Wu Grace, Liu Zhiyu, Guo Jiaqi, Chu Matthew, He Hongjian, Wang Fengbin, Xu Bing
Department of Chemistry, Brandeis University, 415 South St., Waltham, Massachusetts 02454, United States.
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35233, United States.
J Am Chem Soc. 2025 Jan 29;147(4):2978-2983. doi: 10.1021/jacs.4c12150. Epub 2025 Jan 14.
Despite their critical role in context-dependent interactions for protein functions, intrinsically disordered regions (IDRs) are often overlooked for designing peptide assemblies. Here, we exploit IDRs to enable context-dependent heterotypic assemblies of intrinsically disordered peptides, where "context-dependent" refers to assembly behavior driven by interactions with other molecules. By attaching an aromatic segment to oppositely charged intrinsically disordered peptides, we achieve a nanofiber formation. Although the same-charged peptides cannot self-assemble, oppositely charged peptides form heterotypic nanofibers. Cryo-EM analysis reveals a β-sheet arrangement within the ordered core of these nanofibers, conformational heterogeneity, and a disorder-to-order continuum and shows a high number of hydrogen bonds between tyrosine and lysine ε-amine. Additionally, this work demonstrates a post-assembly morphological change resulting from local conformational flexibility. While equal molar mixtures of the charged intrinsically disordered peptides yield nanofibers, doubling the positively charged peptides after assembly produces bundles of nanofibers. Furthermore, reducing the number of aromatic amino acid residues reduces bundle formation. Demonstrating context-dependent self-assembly of intrinsically disordered peptides and revealing atomistic insights into heterotypic assemblies of intrinsically disordered peptides for the first time, this work illustrates a straightforward approach to enable heterotypic intrinsically disordered peptides to self-assemble for the design of adaptive, multifunctional peptide nanomaterials.
尽管内在无序区域（IDRs）在蛋白质功能的上下文依赖性相互作用中起着关键作用，但在设计肽组装体时，它们常常被忽视。在这里，我们利用IDRs实现内在无序肽的上下文依赖性异型组装，其中“上下文依赖性”是指由与其他分子的相互作用驱动的组装行为。通过将一个芳香片段连接到带相反电荷的内在无序肽上，我们实现了纳米纤维的形成。虽然带相同电荷的肽不能自组装，但带相反电荷的肽会形成异型纳米纤维。冷冻电镜分析揭示了这些纳米纤维有序核心内的β-折叠排列、构象异质性以及无序到有序的连续体，并显示酪氨酸和赖氨酸ε-胺之间存在大量氢键。此外，这项工作展示了由局部构象灵活性导致的组装后形态变化。当带电荷的内在无序肽等摩尔混合物产生纳米纤维时，组装后将带正电荷的肽加倍会产生纳米纤维束。此外，减少芳香族氨基酸残基的数量会减少束的形成。这项工作首次证明了内在无序肽的上下文依赖性自组装，并揭示了对内在无序肽异型组装的原子层面见解，阐明了一种直接的方法，使异型内在无序肽能够自组装，用于设计适应性强的多功能肽纳米材料。
