Hierarchical assembly of intrinsically disordered short peptides

The understanding of how short peptide assemblies transit from dis-order to order remains limited due to the lack of atomistic struc-tures. 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 fila-ment 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 pe-riphery 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 pep-tides driven by noncovalent interactions.