Photoswitchable Peptides as Molecular Tools to Encode Structural Order and Disorder in Intracellular Assemblies

TL;DR

This paper introduces a light-sensitive peptide that can switch between forming ordered and disordered structures inside cells, helping study how these structures affect cellular behavior.

Contribution

A photoswitchable isotripeptide is developed to reversibly control intracellular assembly order and disorder from a single molecular scaffold.

Findings

The trans-isomer forms β-sheet-rich nanofibers, while the cis-isomer forms disordered aggregates.

Cell viability correlates with isomer-dependent aggregation and critical aggregation concentrations.

The system enables reversible and robust switching of intracellular assemblies with high photostability.

Abstract

Understanding how self‐assembled structure formation affects cells remains a central challenge in supramolecular chemistry. However, chemical tools that allow access to both ordered and disordered intracellular assemblies from a single molecular scaffold are rare due to design complexity. Here, we present a photoswitchable isotripeptide incorporating an arylazopyrazole (AAP) unit, which undergoes intracellular cleavage to yield a self‐assembling monomer. Upon photoisomerization, the planar trans‐isomer forms β‐sheet‐rich nanofibers with strong aromatic interactions, while the non‐planar cis‐isomer assembles into disordered, random‐coil aggregates lacking aromatic contribution. The structural dynamics of the assemblies are demonstrated by repeated photoswitching between the two states in buffered conditions. Notably, A549 cancer cell viability correlates with the isomer‐dependent assembly behavior and critical aggregation concentrations (CACs): the trans‐isomer, with higher aggregation propensity, exhibits greater cytotoxicity. This photoswitchable peptide system thus provides a powerful platform with fast, reversible and robust switching kinetics, long isomer half‐lives, and high photostability to probe the intracellular consequences of supramolecular order and disorder using a single molecular scaffold.

We present a photoswitchable peptide conjugate which exhibits isomerism‐dependent self‐assembly: the planar trans‐isomer assembles into well‐ordered nanofibers while the non‐planar cis‐isomer yields disordered aggregates. Our study offers a direct visualization on the effects of structure formation inside living cells.

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