Unraveling the Atomistic Mechanism of Electrostatic Lateral Association of Peptide β‐Sheet Structures and Its Role in Nanofiber Growth and Hydrogelation

Guiding molecular assembly of peptides into rationally engineered nanostructures remains a major hurdle against the development of functional peptide‐based nanomaterials. Various non‐covalent interactions come into play to drive the formation and stabilization of these assemblies, of which electrostatic interactions are key. Here, the atomistic mechanisms by which electrostatic interactions contribute toward controlling self‐assembly and lateral association of ultrashort β‐sheet forming peptides are deciphered. Our results show that this is governed by charge distribution and ionic complementarity, both affecting the interaction patterns between charged residues: terminal, core, and/or terminal‐to‐core attraction/repulsion. Controlling electrostatic interactions enabled fine‐tuning nanofiber morphology for the 16 examined peptides, resulting into versatile nanostructures ranging from extended thin fibrils and thick bundles to twisted helical “braids” and short pseudocrystalline nanosheets. This in turn affected the physical appearance and viscoelasticity of the formed materials, varying from turbid colloidal dispersions and viscous solutions to soft and stiff self‐supportive hydrogels, as revealed from oscillatory rheology. Atomistic mechanisms of electrostatic interaction patterns were confirmed by molecular dynamic simulations, validating molecular and nanoscopic characterization of the developed materials. In essence, detailed mechanisms of electrostatic interactions emphasizing the impact of charge distribution and ionic complementarity on self‐assembly, nanostructure formation, and hydrogelation are reported.