Optimized synthetic strategies for the preparation of photoswitchable molecular scaffolds based on stilbene or on thioaurone chromophores and their conformationally directing properties, as studied by computations and by NMR spectroscopy, are addressed. For the stilbene peptidomimetics 1, 2 and 3, the length of connecting linkers between the chromophore and the peptide strands was varied, resulting in photochromic dipeptidomimetics with various flexibility. Building blocks of higher rigidity, based on para-substituted thioaurone (4 and 6) and meta-substituted thioaurone chromophores (5 and 7) are shown to have a stronger conformationally directing effect. Design, synthesis, theoretical and experimental conformational analyses are presented.

A series of peptidomimetics intended to promote the beta-hairpin motif have been studied. Structural variations include a turn region with and without a photoswitchable chromophore, and strands with amino acid side chains supporting various degrees of interstrand interactions for hairpin stabilisation. The propensity of the compounds to form beta-hairpins was evaluated experimentally by NMR spectroscopy, translational self-diffusion studies and CD spectroscopy. In the presence of hairpin stabilising interstrand interactions, the structurally flexible stilbene chromophore appeared to be well compatible with the imposed secondary structure.

A stilbene chromophore has been incorporated into the turn region of a 42 amino acid peptide, linking two helical peptide sections. Spatial proximity between these sections, as well as aggregation into dimers, is required to facilitate the catalytic function of this artificial hydrolase. Photomodulation of the hydrolase activity results in an increase of the activity of 42 % upon switching from the trans to the cis isomer of the chromophore. This is rationalized by a change in the aggregation state of the peptidomimetic, which is supported by diffusion coefficients obtained from PFG-NMR experiments. The results show that incorporation of a small, relatively flexible chromophore into a large peptide is capable of inducing a considerable change in tertiary structure and thus, functionality.

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