Modular peptides from the thermoplastic squid sucker ring teeth form amyloid-like cross-β supramolecular networks

[Display omitted] The hard sucker ring teeth (SRT) from decapodiforme cephalopods, which are located inside the sucker cups lining the arms and tentacles of these species, have recently emerged as a unique model structure for biomimetic structural biopolymers. SRT are entirely composed of modular, block co-polymer-like proteins that self-assemble into a large supramolecular network. In order to unveil the molecular principles behind SRT’s self-assembly and robustness, we describe a combinatorial screening assay that maps the molecular-scale interactions between the most abundant modular peptide blocks of suckerin proteins. By selecting prominent interaction hotspots from this assay, we identified four peptides that exhibited the strongest homo-peptidic interactions, and conducted further in-depth biophysical characterizations complemented by molecular dynamic (MD) simulations to investigate the nature of these interactions. Circular Dichroism (CD) revealed conformations that transitioned from semi-extended poly-proline II (PII) towards β-sheet structure. The peptides spontaneously self-assembled into microfibers enriched with cross β-structures, as evidenced by Fourier-Transform Infrared Spectroscopy (FTIR) and Congo red staining. Nuclear Magnetic Resonance (NMR) experiments identified the residues involved in the hydrogen-bonded network and demonstrated that these self-assembled β-sheet-based fibers exhibit high protection factors that bear resemblance to amyloids. The high stability of the β-sheet network and an amyloid-like model of fibril assembly were supported by MD simulations. The work sheds light on how Nature has evolved modular sequence design for the self-assembly of mechanically robust functional materials, and expands our biomolecular toolkit to prepare load-bearing biomaterials from protein-based block co-polymers and self-assembled peptides. The sucker ring teeth (SRT) located on the arms and tentacles of cephalopods represent as a very promising protein-based biopolymer with the potential to rival silk in biomedical and engineering applications. SRT are made of modular, block co-polymer like proteins (suckerins), which assemble into a semicrystalline polymer reinforced by nano-confined β-sheets, resulting in a supramolecular network with mechanical properties that match those of the strongest engineering polymers. In this study, we aimed to understand the molecular mechanisms behind SRT’s self-assembly and robustness. The most abundant mod