Self-assembled Polypeptoid Nanostructures Revealed by 3-D Cryogenic Electron Microscopy*

Amphiphilic diblock polypeptoids were synthesized with the same block ratio and chain length but different N-terminal capping groups. By tuning these end groups, distinct self-assembled structures, including micelles, nanofibers and nanosheets, can be obtained in polar solvents. The molecular structure of the peptoid nanofibers remains unknown. Low-dose cryogenic electron microscopy micrographs were obtained from the frozen specimens. Single particle analysis was applied to reconstruct the 3-D morphology of the self-assembled nanofibers. The spatial arrangement of the individual molecules was directly observed in the nanofibers with the spatial resolution of ~3.6 Å. The nanofibers, which result from peptoids with an uncapped N-terminus, are shown to exhibit different packing geometries (bilayer vs. interdigitated monolayer) and degrees of order depending on the solvent conditions.  When the N-terminus is acetylated, nanosheets with long-range order are formed. Our imaging approach is robust and enables the direct 3-D visualization of the arrangement of polypeptoid backbones and side chains in the self-assembled nanostructures. It reveals the effect of end group chemistry on the hierarchical structures of polypeptoids at the atomic level.