Engineering Adaptive Supramolecular Polymers: The Role of Palisade Domain Sequence and Alkyl Tail Modulation in Lipopeptide Self-Assembly

Lipopeptides, nature-inspired amphiphiles with modular architectures, derive their functional versatility from the dynamic interplay between hydrophobic and hydrophilic domains. Central to their self-assembly is the interfacial “palisade region”: a structural nexus where molecular packing, flexibility, and supramolecular order are governed by sequence-dependent interactions. In this study, we interrogate how sequence engineering of the palisade domain in peptide amphiphiles dictates the structural dynamics of nanofiber-shaped supramolecular polymers. By systematically modulating the amino acid composition (alanine/glycine ratios) and alkyl tail length (C8 vs. C12), how these molecular “tuning knobs” control secondary structure transitions (beta-sheet/alpha-helix) and intermolecular cohesion was investigated. It was hypothesize that alanine-rich sequences, with their propensity for beta-sheet formation and rigid hydrogen-bonded networks, will stabilize fibrillar rigidity, whereas glycine’s conformational flexibility will enhance molecular mobility, yielding softer, adaptive assemblies. To resolve these structural and dynamic effects, small-angle neutron scattering (SANS) with contrast-matching strategies (H2O/D2O solvents, deuterated lipopeptides), would enable real-time, solvent-visible interrogation of self-assembly pathways in physiologically relevant environments.