Peptide-based supramolecular systems chemistry seeks to mimic the ability of life forms to use conserved sets of building blocks and chemical reactions to achieve a bewildering array of functions. Building on the design principles for short peptide-based nanomaterials with properties, such as self-assembly, recognition, catalysis, and actuation, are increasingly available. Peptide-based supramolecular systems chemistry is starting to address the far greater challenge of systems-level design to access complex functions that emerge when multiple reactions and interactions are coordinated and integrated. We discuss key features relevant to systems-level design, including regulating supramolecular order and disorder, development of active and adaptive systems by considering kinetic and thermodynamic design aspects and combinatorial dynamic covalent and noncovalent interactions. Finally, we discuss how structural and dynamic design concepts, including preorganization and induced fit, are critical to the ability to develop adaptive materials with adaptive and tunable photonic, electronic, and catalytic properties. Finally, we highlight examples where multiple features are combined, resulting in chemical systems and materials that display adaptive properties that cannot be achieved without this level of integration.

Water‐responsive (WR) materials that reversibly deform in response to relative humidity (RH) changes are gaining increasing interest for their potential in energy harvesting and soft robotics applications. Despite progress, there are significant gaps in the understanding of how supramolecular structure underpins the reconfiguration and performance of WR materials. Here, three crystals are compared based on the amino acid phenylalanine (F) that contain water channels and F packing domains that are either layered (F), continuously connected (phenylalanyl‐phenylalanine, FF), or isolated (histidyl‐tyrosyl‐phenylalanine, HYF). Hydration‐induced reconfiguration is analyzed through changes in hydrogen‐bond interactions and aromatic zipper topology. F crystals show the greatest WR deformation (WR energy density of 19.8 MJ m−3) followed by HYF (6.5 MJ m−3), while FF exhibits no observable response. The difference in water‐responsiveness strongly correlates to the deformability of aromatic regions, with FF crystals being too stiff to deform, whereas HYF is too soft to efficiently transfer water tension to external loads.  These findings reveal aromatic topology design rules for WR crystals and provide insight into general mechanisms of high‐performance WR actuation. Moreover, the best‐performing crystal, F emerges as an efficient WR material for applications at scale and low cost.