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 alpha-helices or -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-block-poly(S-ethylsulfonyl-DL-cysteine) (pSar-b-p-(DL)Cys), enantiopure polysarcosine-block-poly(S-ethylsulfonyl-L-cysteine) (pSar-b-p(L)Cys), and polysarcosine-block-poly(S-ethylsulfonyl-L-homocysteine) (pSar-b-p(L)Hcy) was prepared by N-carboxyanhydride polymerization. The secondary structure of the peptide segment varies from a-helices (pSar-b-p(L)Hcy) to antiparallel beta-sheets (pSar-b-p(L)Cys) and disrupted beta-sheets (pSar-b-p(DL)Cys). When subjected to nanoprecipitation, copolymers with antiparallel beta-sheets display the strongest tendency to self-assemble, whereas disrupted beta-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.