Controlling order and dynamics in peptide assemblies by molecular design and light
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Abstract
The transition between order and disorder is a central element governing self-assembly in both natural and synthetic systems. However, achieving control over assembly pathways, reversibility and the rational design of functional structural order remain challenging, particularly under far-from-equilibrium and biologically relevant conditions. Although numerous peptide-based self-assembling systems have been reported, rational design principles linking molecular structure to dynamic supramolecular behavior remain insufficiently explored. In this thesis, minimalistic peptide sequences are employed to investigate how subtle molecular design parameters govern supramolecular order and disorder in a stimulus-responsive manner. Systematic analysis of linker flexibility is used to identify its relevance for effective intermolecular interactions and the formation of ordered assemblies. Subsequently, light is introduced as a non-invasive external stimulus offering high spatiotemporal precision to actively regulate order-disorder transitions. Both irreversible and reversible photoresponsive strategies are explored to probe assembly pathways and non-equilibrium behavior. Building on these concepts, photoreversible peptide systems are developed that enable repeated switching between ordered and disordered states through photoisomerization. Using isopeptide chemistry, the peptide scaffold is further extended to facilitate cellular uptake, while glutathione-responsive motifs allow these systems to exhibit intracellular activity in such biological environments. This approach enables correlations between supramolecular organization and cellular response to be examined. Collectively, the results demonstrate that molecular-level design enables active control over peptide self-assembly pathways beyond static equilibrium structures. This work establishes design principles for adaptive supramolecular peptide systems and contributes to bridging supramolecular physical chemistry with dynamic behavior in complex, life-inspired environments.