Amyloid engineering - how terminal capping modifies morphology and secondary structure of supramolecular peptide aggregates.

The effects of peptide N- and C-termini on aggregation behavior have been scarcely studied. Herein, we examine (105-115) peptide fragments of transthyretin (TTR) containing various functional groups at both termini and study their impact on the morphology and the secondary structure. We synthesized TTR(105-115) peptides functionalized with α-amino (H-), N -acetyl-α-amino (Ac-) or N , N -dimethyl-α-amino (DiMe-) groups at the N-terminus, and with amide (-NH 2 ) or carboxyl (-OH) functions at the C-terminus. We also investigated quasi-racemic mixtures by mixing the L-enantiomers with the D-enantiomer capped by H- and -NH 2 groups. We observed that fibril formation is promoted by the sufficient number of hydrogen bonds at peptides' termini. Moreover, the final morphology of the aggregates can be controlled by the functional groups at the N-terminus. Remarkably, all quasi-racemic mixtures resulted in the robust formation of fibrils. Overall, this work illustrates how modifications of peptide termini may help to engineer supramolecular aggregates with a predicted morphology.