Sequence‐Tunable Phase Behavior and Intrinsic Fluorescence in Dynamically Interacting Peptides

• Published in: Angewandte Chemie International Edition 2023-12, Vol.62 (50), p.e202311479-n/a
• Main Authors: Sementa, Deborah, Dave, Dhwanit, Fisher, Rachel S., Wang, Tong, Elbaum‐Garfinkle, Shana, Ulijn, Rein V.
• Format: Article
• Language: English
• Subjects: Amino Acids; Amino Acids - chemistry; Biomimetics; Condensates; Confocal microscopy; Fluorescence; Liquid-Liquid Phase Separation; Molecular Dynamics; Peptides; Peptides - chemistry
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202311479

A conceptual framework towards understanding biological condensed phases is emerging, derived from biological, biomimetic, and synthetic sequences. However, de novo peptide condensate design remains a challenge due to an incomplete understanding of the structural and interactive complexity. We designed peptide modules based on a simple repeat motif composed of tripeptide spacers (GSG, SGS, GLG) interspersed with adhesive amino acids (R/H and Y). We show, using sequence editing and a combination of computation and experiment, that n→π* interactions in GLG backbones are a dominant factor in providing sufficient backbone structure, which in turn regulates the water interface, collectively promoting liquid droplet formation. Moreover, these R(GLG)Y and H(GLG)Y condensates unexpectedly display sequence‐dependent emission that is a consequence of their non‐covalent network interactions, and readily observable by confocal microscopy. The de‐novo rational design of short peptide motifs that assemble into fluorescent condensates with sequence‐dependent phase behavior is investigated. Integrating experiments and molecular dynamics (MD) simulations, the role of sidechain solvation, n‐π* interactions, and hydrogen bonding are highlighted through systematic sequence variations on an identical peptide backbone scaffold.