Secondary Structure-Driven Self-Assembly of Thiol-Reactive Polypept(o)ides.

Secondary structure formation differentiates polypeptides from most of the other synthetic polymers, and the transitions from random coils to rod-like α-helices or β-sheets represent an additional parameter to direct self-assembly and the morphology of nanostructures. We investigated the influence of distinct secondary structures on the self-assembly of reactive amphiphilic polypept(o)ides. The individual morphologies can be preserved by core cross-linking via chemoselective disulfide bond formation. A series of thiol-responsive copolymers of racemic polysarcosine--poly(-ethylsulfonyl-dl-cysteine) (pSar--p(dl)Cys), enantiopure polysarcosine--poly(-ethylsulfonyl-l-cysteine) (pSar--p(l)Cys), and polysarcosine--poly(-ethylsulfonyl-l-homocysteine) (pSar--p(l)Hcy) was prepared by -carboxyanhydride polymerization. The secondary structure of the peptide segment varies from α-helices (pSar--p(l)Hcy) to antiparallel β-sheets (pSar--p(l)Cys) and disrupted β-sheets (pSar--p(dl)Cys). When subjected to nanoprecipitation, copolymers with antiparallel β-sheets display the strongest tendency to self-assemble, whereas disrupted β-sheets hardly induce aggregation. This translates to worm-like micelles, solely spherical micelles, or ellipsoidal structures, as analyzed by atomic force microscopy and cryogenic transmission electron microscopy, which underlines the potential of secondary structure-driven self-assembly of synthetic polypeptides.