Amyloid supramolecular assemblies have found widespread exploitation as ordered nanomaterials in a range of applications from materials science to biotechnology. New strategies are, however, required for understanding and promoting mature fibril formation from simple monomer motifs through easy and scalable processes. Noncovalent interactions are key to forming and holding the amyloid structure together. On the other hand, the halogen bond has never been used purposefully to achieve control over amyloid self-assembly. Here we show that single atom replacement of hydrogen with iodine, a halogen-bond donor, in the human calcitonin-derived amyloidogenic fragment DFNKF results in a super-gelator peptide, which forms a strong and shape-persistent hydrogel at 30-fold lower concentration than the wild-type pentapeptide. This is remarkable for such a modest perturbation in structure. Iodination of aromatic amino acids may thus develop as a general strategy for the design of new hydrogels from unprotected peptides and without using organic solvents.

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Although intensively studied, the high‐resolution crystal structure of the peptide DFNKF, the core‐segment of human calcitonin, has never been described. Here we report how the use of iodination as a strategy to promote crystallisation and facilitate phase determination, allowed us to solve, for the first time, the single‐crystal X‐ray structure of a DFNKF derivative. Computational studies suggest that both the iodinated and the wild‐type peptides populate very similar conformations. Furthermore, the conformer found in the solid‐state structure is one of the most populated in solution, making the crystal structure a reliable model for the peptide in solution. The crystal structure of DFNKF(I) confirms the overall features of the amyloid cross‐β spine and highlights how aromatic–aromatic interactions are important structural factors in the self‐assembly of this peptide. A detailed analysis of such interactions is reported.

What is the most significant result of this study?Iodination of the benzene ring p-position of Phe2 in the human calcitonin-derived amyloidogenic sequence DFNKF allowed its first ever high-resolution crystal structure determination. The structure unveils aromatic-aromatic interactions as key structural factors. This is important as it may shed new light on the formation mechanism of amyloid fibrils. Furthermore, we demonstrate that iodination promotes peptide crystallization by introducing secondary contacts that stabilize the overall packing.What time consuming dead-ends delayed the results before this breakthrough?Obtaining high-quality single crystals of fibril-forming peptides is rather difficult. To obtain the reported crystal required six months and the crystals were tiny,w hich complicated the data acquisition.What other topics are you working on at the moment?Besides our research on protein and peptide crystallography,w e are working on the effects of halogenation on the self-assembly of amyloidogenic peptides. In particular,w ea re exploiting halogen bonding as key noncovalent interaction to direct self-assembly and nanostructure control in peptide and proteins.Invited for the cover of this issue is the group of Pierangelo Metrangoloa tt he Politecnico di Milano. The image depicts the steric zipper formed by the amyloidogenic peptide, DFNKF. Read the full text of the article at