Hierarchical assembly of intrinsically disordered short peptides

Abstract

•Hydrophobic interactions drive IDPs to self-assemble to form assemblies •Cryo-EM reveals the atomic structures of fibrillar assemblies of IDPs •Calcium ion switches the symmetry of IDP filaments from C1 to C2 •Interfibrillar interactions confer filament bundles as higher-order assemblies The understanding of how short peptide assemblies transit from disorder to order remains limited due to the lack of atomistic structures. Here, we report the cryo-EM structure of the nanofibers short intrinsically disordered peptides (IDPs). On lowering pH or adding calcium ions, the IDP transitions from individual nanoparticles to nanofibers containing an aromatic core and a disordered periphery were composed of 2–5 amino acids. Protonating the phosphate or adding more metal ions further assembles the nanofibers into filament bundles. The assemblies of the IDP analogs with controlled chemistry, such as phosphorylation site, hydrophobic interactions, and sequences, indicate that metal ions interact with the flexible periphery of the nanoparticles of the IDPs to form fibrils and enhance the interfibrillar interactions to form filament bundles. Illustrating that an IDP self-assembles from disorder to order, this work offers atomistic molecular insights to understand assemblies of short peptides driven by noncovalent interactions. The understanding of how short peptide assemblies transit from disorder to order remains limited due to the lack of atomistic structures. Here, we report the cryo-EM structure of the nanofibers short intrinsically disordered peptides (IDPs). On lowering pH or adding calcium ions, the IDP transitions from individual nanoparticles to nanofibers containing an aromatic core and a disordered periphery were composed of 2–5 amino acids. Protonating the phosphate or adding more metal ions further assembles the nanofibers into filament bundles. The assemblies of the IDP analogs with controlled chemistry, such as phosphorylation site, hydrophobic interactions, and sequences, indicate that metal ions interact with the flexible periphery of the nanoparticles of the IDPs to form fibrils and enhance the interfibrillar interactions to form filament bundles. Illustrating that an IDP self-assembles from disorder to order, this work offers atomistic molecular insights to understand assemblies of short peptides driven by noncovalent interactions.