Rational design of a nanoscale helical scaffold derived from self-assembly of a dimeric coiled coil motif

We describe a model for the design of synthetic α-helical peptides that are competent for self-assembly into structurally defined supramolecular fibrils on the basis of architectural features that have been programmed into the peptide sequence. In order to test the validity of this experimental model, we have synthesized an oligopeptide that was designed to conform to this model and to self-assemble into an α-helical fibril in which the structural sub-units that comprise the fibril corresponded to coiled coil dimers. Peptide was prepared via conventional solid-phase peptide synthesis and was composed of 42 amino acid residues such that the sequence defined six distinct heptad repeats of a coiled coil structure. The sequence of was designed to adopt an α-helical conformation in which the helical protomers self-associate in a parallel orientation with a staggered orientation between adjacent peptides that corresponded to an axial displacement of three heptads. The self-assembly of peptide was examined at varying levels of structural hierarchy for compliance of the observed structures with the experimental model. Circular dichroism spectroscopy provided evidence for an α-helical coiled coil structure for in aqueous solution, which could be reversibly denatured through thermal methods. TEM measurements indicated the formation of long aspect-ratio fibers of uniform diameter from aqueous solutions of , however the dimensions of the fibers suggested that lateral association occurred between the fibrils corresponding to the 2-stranded helical bundles. The α-helical coiled coil structure was confirmed in the solid-state for fibers derived from self-assembly of by a combination of wide-angle X-ray diffraction and 13C CP/MAS NMR spectroscopy. SANS and synchrotron SAXS measurements on dilute aqueous solutions of provided a fibril diameter that corresponded to the lateral dimensions estimated for a dimeric coiled coil assembly on the basis of structural determinations of model peptides.