Backbone‐Constrained Tripeptides Enable Sequence Control of Solid‐State Dynamics

Abstract

ABSTRACT Understanding how peptide sequence relates to supramolecular dynamics and consequent solid‐state material properties remains a central challenge for rational peptide materials design. Here, we use N‐terminal proline as a strategic conformational constraint in minimalist tripeptides ( PXX ; P = proline, X = phenylalanine (F) or tryptophan (W)) to isolate side‐chain contributions from backbone and show that simple aromatic exchange dictates crystallization pathways and solid‐state dynamics. In this design, proline rigidifies the backbone, the central residue supports assembly, and the C‐terminal aromatic residue dictates conformational adaptability. Combining molecular dynamics simulations with NMR and fluorescence spectroscopy, we show that peptides with W at the C‐terminus, with a diverse interaction space, display shallow energy landscapes with multiple accessible states, whereas a C‐terminal F, with a stringent hydrophobic nature and limited interaction space, restricts the peptide into fewer conformations. As a result, PXF peptides form soluble supramolecular aggregates, while PXW peptides access more adaptable conformations that promote crystallization. Solid‐state characterization reveals that these sequence‐encoded supramolecular dynamics directly influence bulk properties: W‐containing peptides form stiff crystals with dynamic, wettable surfaces, whereas F analogues yield static, hydrophobic materials. Together, these results establish how aromatic‐residues dictate supramolecular assembly and crystallization, offering a straightforward approach to engineering dynamic properties in solid‐state peptide materials.