Harnessing Amino Acid Modularity for Programmable Function in Covalent Peptide Assemblies.

Abstract

Covalent peptide assembly leverages robust covalent bonds and dynamic non-covalent interactions to provide enhanced stability and introduce diverse functionalities. Nevertheless, it remains significantly challenging to achieve modular control over the structural diversity and functional complexity while elucidating how specific amino acid sequences contribute to these processes. Here, the systematic encoding of peptide derivative characteristics is demonstrated through amino acid modularity to enable precise control over both the structural diversity and functional complexity in covalent peptide assemblies. By systematically screening single amino acid substitutions in pentapeptides using tyrosine crosslinking, a diverse library of peptide constructs is developed. Each construct is tailored to exhibit distinct properties, including charge repulsion, aggregation-induced quenching, disassembly behavior, and redox responsiveness. The strategic manipulation of sequence composition, both in individual assemblies and combinatorial systems, enables programmable control over the structural diversity and functional complexity. This approach yields various module-specific functions, including frustrated growth, hierarchical hollow architecture formation, affinity enrichment, stimuli-responsive behavior, and fluorescence signal amplification. This work establishes a framework for the design of modular peptide materials with programmable functionalities, advancing the development of next-generation multicomponent peptide assembly technologies characterized by unprecedented complexity and adaptability.