Herein we describe the use of dynamic combinatorial chemistry to self-assemble complex coiled coil motifs. We amide-coupled a series of peptides designed to form homodimeric coiled coils with 3,5-dithiobenzoic acid (B) at the N-terminus and then allowed each B-peptide to undergo disulfide exchange. In the absence of peptide, monomer B forms cyclic trimers and tetramers, and thus we expected that addition of the peptide to monomer B would shift the equilibrium towards the tetramer to maximize coiled coil formation. Unexpectedly, we found that internal templation of the B-peptide through coiled coil formation shifts the equilibrium towards larger macrocycles up to 13 B-peptide subunits, with a preference for 4, 7, and 10-membered macrocycles. These macrocyclic assemblies display greater helicity and thermal stability relative to intermolecular coiled coil homodimer controls. The preference for large macrocycles is driven by the strength of the coiled coil, as increasing the coiled coil affinity increases the fraction of larger macrocycles. This system represents a new approach towards the development of complex peptide and protein assemblies.
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Hierarchical Assembly of a Tetrameric Coiled‐Coil Into Cuboid Structures
ABSTRACT A tetrameric coiled‐coil peptide,TetNL, is used herein as a building block for hierarchical assembly into higher order structures. Assembly within phosphate buffer (pH 7.4) led to the rapid formation of micron‐sized fibers and cuboid structures, a process that could be shifted toward cuboid formation with agitation during the assembly process. Investigation of the packing of the cuboid assemblies by TEM demonstrated a regular banding pattern (4.6 nm) within the structures that was perpendicular to the length of the cuboids, a value that supports an end‐to end organization of the tetrameric coiled coils along the blocks. SWAXS analysis supports that the internal packing of the tetrameric coiled coil building blocks is a close‐packed hexagonal structure. These data represent an interesting comparison with a trimeric coiled coil peptide,TriNL, that forms hollow nanotubes with the same internal hexagonal packing. ModifiedTriNLhas been used to generate numerous unique morphologies, and the data presented herein provide a distinct tetrameric building block that can also be exploited in this manner.
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- Award ID(s):
- 2108722
- PAR ID:
- 10626934
- Publisher / Repository:
- Wiley
- Date Published:
- Journal Name:
- Peptide Science
- Volume:
- 117
- Issue:
- 1
- ISSN:
- 2475-8817
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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