ABSTRACT
Peptide‐based assemblies have gained increasing attention in different areas of nanotechnology, drug delivery and molecular biology. Among these, non‐natural β‐peptide scaffolds are particularly promising, as their programmable and diverse secondary structures, high metabolic stability and strong self‐association propensity can be easily exploited to create variable constructs. We have recently demonstrated that heterochiral, acyclic β 3 ‐peptides assembled into striped lamellar nanostructures that induced antibacterial activity. The process of this assembly formation could be exploited in diverse areas, however identifying oligomerisation stages, and more importantly, controlling the spontaneous process at different levels is still lacking. In this study, a set of analogues heterochiral hexameric β 3 ‐peptide sequences was investigated to understand how systematic, small variations of the sequences, such as single point mutation or N‐terminal chemical modification, can influence the resulting assemblies and allow the control of formed morphologies. TEM and cryo‐EM combined with molecular dynamics simulation enabled the identification and differentiation of morphological stages throughout the entire multi‐step process. Depending on the position of the sequence modifications, the self‐assembled structures formed small oligomers, individual protofibrils, extended, flat lamellae, bundles and macroscopic clusters. These results outline how the self‐assembly process of short heterochiral β‐peptides can be qualitatively fine‐tuned by sequence modifications, which contribute to understanding the general peptide assembly processes for their fibrillar morphologies.
}, year = {2026}, journal = {Aggregate}, volume = {7}, issn = {2692-4560, 2692-4560}, doi = {10.1002/agt2.70282}, }