Self-assembling peptides are being widely studied for applications both in health and nanotechnology. Their uses are closely linked to their modes of self-organization, which determine the functional nanostructures that they form. Research in this area stemmed from the ability of hydrophobic (tri)peptides to stack into anisotropic structures (e.g., fibrils) with an amphipathic architecture that provides gelling ability and stability in water. Recent developments included a more diverse set of amino acids with interesting chemical features and functional groups on the side chains to program the supramolecular behaviour of heterochiral short peptides in new ways. As an example, two structural elements that direct supramolecular behavior in divergent directions were combined in one sequence: proline as a β-breaker and the β-structure-associated diphenylalanine motif. The inherent tension due to these conflicting self-assembly instructions could be resolved by amino acid chirality. Stereoconfiguration determined the ability of each stereoisomer to self-associate into diverse nanostructures, including nanoparticles, nanotapes, or fibrils, which yielded hydrogels with gel-to-sol transition at a physiologically relevant temperature. Single-crystal structures and all-atom molecular dynamics simulations elucidated the ability of each peptide to establish key interactions to form long-range assemblies (i,e., stacks leading to gelling fibrils), medium-range assemblies (i.e., stacks yielding nanotapes), or short-range assemblies (i.e., antiparallel dimers or trimers that further associated into nanoparticles). Importantly, diphenylalanine is known to serve as a binding anchor for pathological amyloids, potentially allowing to use these heterochiral peptides to inhibit the fibrillization of pathological amyloids, as demonstrated in vitro on the Alzheimer’s disease-associated Aβ(1–42) peptide.
Overall, this line of research is evolving from simple hydrophobic structures to a more diverse set of functional groups to enable a wide variety of functions and expand the supramolecular level of complexity that can be attained from very simple building blocks based on biomolecules.

Michele Melchionna

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