Preserving Structurally Labile Peptide Nanosheets After Molecular Functionalization of the Self‐Assembling Peptides

Abstract

A significant challenge in creating supramolecular materials is that conjugating molecular functionalities to building blocks often results in dissociation or undesired morphological transformation of their assemblies. Here we present a facile strategy to preserve structurally labile peptide assemblies after molecular modification of the self‐assembling peptides. Sheet‐forming peptides are designed to afford a staggered alignment with the segments bearing chemical modification sites protruding from the sheet surfaces. The staggered assembly allows for simultaneous separation of attached molecules from each other and from the underlying assembly motifs. Strikingly, using PEGs as the external molecules, PEG400‐ and PEG700‐peptide conjugates directly self‐associate into nanosheets with the PEG chains localized on the sheet surfaces. In contrast, the sheet formation based on in‐register lateral packing of peptides does not recur upon the peptide PEGylation. This strategy allows for fabrication of densely modified assemblies with a variety of molecules, as demonstrated using biotin (hydrophobic molecule), c(RGDfK) (cyclic pentapeptide), and nucleic acid aptamer (negatively charged ssDNA). The staggered co‐assembly also enables extended tunability of the amount/density of surface molecules, as exemplified by screening ligand‐appended assemblies for cell targeting. This study paves the way for functionalization of historically challenging fragile assemblies while maintaining their overall morphology.

Two-Dimensional Molecular Architectonics through Controlled Noncovalent Interactions: Structure, Functional Properties, and Applications

“…A recent study elucidated the role of sequence-specific electrostatic interactions in facilitating the staggered and in-register lateral alignment of sheet-forming coiled-coils. 64 The synthesized peptide sequences (37−39) exhibited a preference for trimer formation, with hydrophobic cores adopting a knobs-into-holes configuration. Peripheral residues K and E drove antiparallel lateral packing, fostering the formation of 2D sheet structures via complementary electrostatic interactions (Figure 4m).…”

“…The honeycomb structure was formed due to packing frustration that was counterbalanced by the helical channels at defect sites of the lattice (Figure l). A recent study elucidated the role of sequence-specific electrostatic interactions in facilitating the staggered and in-register lateral alignment of sheet-forming coiled-coils . The synthesized peptide sequences ( 37 – 39 ) exhibited a preference for trimer formation, with hydrophobic cores adopting a knobs-into-holes configuration.…”

“…Copyright 2017, 2020, and 2016, respectively, American Chemical Society. Panels (m) and (n–q) were adapted with permission from ref and ref , respectively. Copyright 2024 and 2024, respectively, Wiley-VCH.…”