Elucidating Self-Assembly Tunability via a Designer Zwitterionic Surfactant-like Peptide

Although complex electrostatic interactions play a vital role in defining protein architectures, it remains a challenge to exploit them to precisely tune peptide nanostructures instead of trigger assembly in the field of peptide self-assembly due to the inherent difficulty in accurately determining the protonation/deprotonation states of charge residues. We here design a zwitterionic β-sheet peptide Ac-I₃GGHE-NH₂ containing a basic His and an acidic Glu residue, whose charged states (cationic, zwitterionic, and anionic) were found to be not only dependent on solution pH but also closely related to peptide concentration. As a result, the nature and magnitude of intermolecular electrostatic interactions of Ac-I₃GGHE-NH₂, as well as specific His-His interactions, were orchestrated well by varying the two solution conditions, eventually leading to different assembled architectures. Such a work not only helps understand the multiple roles of electrostatic interactions in peptide assembly but also provides a blueprint for precisely harnessing peptide nanostructures via complex electrostatic interactions.