Perturbation effect of single polar group substitution on the Self-Association of amphiphilic peptide helices

As an important attempt towards creating hierarchical structures more like nature, the peptide is employed as a building block to build supramolecular architectures. An emerging question is whether the molecular mechanism of self-assembly obtained from the small molecule system, e.g., the driving forces of assembly are conventionally regarded as pairwise-additive, can be manifested in the self-association of biologically relevant amphiphilic peptides. A peptide, KRT-R, was derived from the 120-144 segment of keratin 14. The single cation-to-cation substitution with KRT-R at the site of 125 from arginine (R) to either lysine (K) or histidine (H) results in the peptide helices, KRT-K and KRT-H, sharing 96% sequence identity. These KRT-derived peptides possess similarities in the folding structures but exhibit divergent self-assembled structures. KRT-R and KRT-K self-assemble into sheets and fibrils, respectively. Whereas KRT-H associates into heterogeneous structures, including sheets, particles, and branched networks. The intrinsic tyrosine fluorescence spectroscopy measurements with the KRT-derived peptides within a temperature range of 25 °C to 95 °C reveal that the heating-triggered structural transitions of KRT-derived peptides are divergent. The alternation of single cationic residue changes the thermodynamic signature of peptide assemblies upon heating. A chemical denaturation experiment with KRT-derived peptides indicates that the intermolecular interactions that govern the supramolecular architectures formed by peptides are distinct. Overall, our work demonstrates the contribution of the interplay among various noncovalent interactions to supramolecular assembly.