Hydrogen-bonding interactions in ferrocene-peptide conjugates containing valine

The synthesis and characterization of a series of ferrocene (Fc) peptide conjugates containing the amino acid valine is reported, where the peptide substituents are part of the hydrophobic sequence of the amyloid β-peptide. The hydrogen-bonding (H-bonding) interaction in these compounds is studied by variable temperature 1H NMR spectroscopy. The solid-state structures, determined by single crystal X-ray crystallography, of two of the conjugates (Fc[CO-Leu-Val-OMe]21 and Fc[CO-Gly-Val-OH]26) are reported. Both structures are stabilized by intramolecular H-bonds exhibiting the familiar “Herrick motif” involving the proximal amide NH and the amide CO of the adjacent amino acid. This motif is sufficiently rigid and is maintained in solution as suggested by CD studies. However, the intermolecular H-bonding patterns observed on conjugates 1 and 6 are significantly different resulting in very different supramolecular architectures. For conjugate 1, a more conventional set of head-to-tail stacking interactions which is stabilized by β-sheet-like H-bonding interactions between the individual molecules is observed. However, for conjugate 6, the presence of the C-terminal acid group and presumably the flexibility of the Gly linker enables the formation of a more open structure that contains hydrophobic channels occupied by solvent molecules.

Self-assembly of valine-containing ferrocene-peptide conjugates via intermolecular hydrogen bonding results in the formation of supramolecular architectures. Figure optionsDownload as PowerPoint slideResearch highlights
► Synthesis and characterization of a series of valine-containing ferrocene-peptide conjugates.
► Association of these conjugates occurs via intermolecular hydrogen bonding.
► Presence of C-terminal carboxylates leads to the formation of peptide stacks with solvent filled voids.