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 self-assemble 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 pH-triggered 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.
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The synchrotron SAXS data was collected at beamline P12 operated by EMBL Hamburg at the PETRA III storage ring (DESY, Hamburg, Germany), and the SOLEIL synchrotron facility for time on Beamline SWING and at beamline B21 at Diamond Light Source. The authors thank Haydyn Mertens (DESY), Thomas Bizien (Soleil), Nathan Cowieson, and Charlotte Edwards-Gayle (Diamond Light Source) for the assistance in using the beamlines. This work was supported by the National Science Foundation under Grant No. 1715627, the United States-Israel Bi-national Science Foundation under Grant No. 2020787, and the Israel Science Foundation under Grants No. 1454/20. The authors also acknowledge the fruitful discussions with Vladimir Uversky, Ram Avinery, and Uri Raviv.
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