Molecular design of stapled pentapeptides as building blocks of self-assembled coiled coil–like fibers

Abstract

Peptide self-assembly inspired by natural superhelical coiled coils has been actively pursued but remains challenging due to limited helicity of short peptides. Side chain stapling can strengthen short helices but is unexplored in design of self-assembled helical nanofibers as it is unknown how staples could be adapted to coiled coil architecture. Here, we demonstrate the feasibility of this design for pentapeptides using a computational method capable of predicting helicity and fiber-forming tendency of stapled peptides containing noncoded amino acids. Experiments showed that the best candidates, which carried an aromatically substituted staple and phenylalanine analogs, displayed exceptional helicity and assembled into nanofibers via specific head-to-tail hydrogen bonding and packing between staple and noncoded side chains. The fibers exhibited sheet-of-helix structures resembling the recently found collapsed coiled coils whose formation was sensitive to side chain flexibility. This study expands the chemical space of coiled coil assemblies and provides guidance for their design.

Peptide-based nanomaterials: Self-assembly, properties and applications

“…To drive the directional self-assembly, they anchored two phenylalanines at the first and fourth positions of the peptides, and the intermolecular aromatic interactions provided by the side chains of phenylalanines dominate the dimeric interface of the conformers [ 23 ].Compared to linear short helical peptides, constrained peptides with crosslinkers represent a class of more intriguing ultrashort helical peptide building blocks for peptide assembly due to their hyperstability and low molecular free energy. Based on a peptide scaffold with a thioether-containing side chain staple, Li et al designed the coiled coil nanofibers from peptides that contain five amino acids [ 24 , 25 ]. Lee et al showed that peptide self-assembly mediated by β-sheet could stabilize α-helix artfully, thus making the peptide self-assemble to nanostructures in aqueous [ 26 ].…”

Self-assembling peptides-based nano-cargos for targeted chemotherapy and immunotherapy of tumors: recent developments, challenges, and future perspectives

“…Li et al. constructed coiled nanofibers from five amino acids containing peptides scaffold with a thioether containing side chain (Hu et al., 2016 ; Jiang et al., 2021 ). RADA16-I peptide made of aspartic acid, alanine, and arginine form β-sheet structure and self-assembles into nanofibers.…”

Self-Assembling Peptides: From Design to Biomedical Applications

“…Another strategy involves the use of side chain stapling able to enhance the helical tendency [ 53 , 54 , 55 , 56 ]. Very recently, a thioether-containing side chain staple was shown to be able to promote the folding of 5-mer peptides into canonical helical structures able to evolve into coiled coil nanofibers [ 57 ].…”