Self-Assembly of Tunable Intrinsically Disordered Peptide Amphiphiles

Intrinsically disordered peptide amphiphiles (IDPAs) present a novel class of synthetic conjugates that consist of short hydrophilic polypeptides anchored to hydrocarbon chains. These hybrid polymer-lipid block constructs spontaneously selfassemble into dispersed nanoscopic aggregates or ordered mesophases in aqueous solution due to hydrophobic interactions. Yet, the possible sequence variations and their influence on the self-assembly structures are vast and have hardly been explored. Here, we measure the nanoscopic self-assembled structures of four IDPA systems that differ by their amino acid sequence. We show that permutations in the charge pattern along the sequence remarkably alter the headgroup conformation and consequently alter the pHtriggered phase transitions between spherical, cylindrical micelles and hexagonal condensed phases. We demonstrate that even a single amino acid mutation is sufficient to tune structural transitions in the condensed IDPA mesophases, while peptide conformations remain unfolded and disordered. Furthermore, alteration of the peptide sequence can render IDPAs to become susceptible to enzymatic cleavage and induce enzymatically activated phase transitions. These results hold great potential for embedding multiple functionalities into lipid nanoparticle delivery systems by incorporating IDPAs with the desired properties.

Automated summary

Intrinsically disordered peptide amphiphiles (IDPAs) are a novel class of synthetic conjugates that self-assemble into dispersed nanoscopic aggregates or ordered mesophases. Sequence variations in the IDPA systems can significantly alter the headgroup conformation and induce phase transitions, and alterations in the peptide sequence can render IDPAs susceptible to enzymatic cleavage and induce enzymatically activated phase transitions.