Self-assembly of wide peptide nanoribbons via the formation of nonpolar zippers between β-sheets

Abstract

Because zipper motifs between complementary sidechains can allow molecular order to be maintained over larger length scales, they hold great promise for the preparation of hierarchical peptide self-assemblies with long-range ordering. Although polar zippers based on sidechain-sidechain hydrogen bonding have been demonstrated to promote significant lamination of β-sheets into wide and flat nanoribbons, it remains a challenge to achieve such well-defined nanostructures through nonpolar zippers. In this study, we designed a series of short amphiphilic peptides Ac-I3XGK-NH2, where X at the intramolecular hydrophobic/hydrophilic interface denotes different hydrophobic residues. Microscopic imaging and neutron scattering measurements indicated that only Ac-I3VGK-NH2 could self-assemble into wide and uniform nanoribbons. Spectroscopic and solid-state NMR analyses revealed that the peptide adopted an anti-parallel β-sheet secondary structure with a two-residue shifting. Under such a molecular conformation and alignment, homogenous and extensive nonpolar zippers between β-sheets, consisting of alternating Val4-Ile3 and Ile2-Ile1 sidechain contacts, would be formed, leading to significant β-sheet lamination that can cause wide and flat nanoribbon assembly. Finally, the failure of the peptide variants to form wide and flat nanoribbons indicated a stringent requirement of extensive nonpolar zipper formation between β-sheets for primary sequence, especially the interaction mode of hydrophobic sidechains.