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Disulfide hydrogels, derived from cysteine‐based redox systems, exhibit active self‐assembly properties driven by reversible disulfide bond formation, making them a versatile platform for dynamic material design. Detailed cryogenic electron microscopy (cryo‐EM) analysis reveals a consistent fiber diameter of 5.4 nm for individual fibers. Using cryo‐EM‐informed radial positional restraints, all‐atom molecular dynamics (MD) simulations are employed to reproduce fibers with dimensions closely matching experimental observations, validated further through simulated cryo‐EM images. The MD simulations reveal that the disulfide gelator (CSSC) predominantly adopts an open conformation, with hydrogen bonds emerging as the key intermolecular force stabilizing the fibers. Notably, intermolecular interactions are found to be higher at 70% conversion to the disulfide gelator compared with 100%, comparable with past unrestrained simulations. Water molecules and solute‐water hydrogen bonds are present throughout the fiber, indicating that the fiber remains hydrated. These findings underscore the potential role of the thiol precursor CSH in stabilizing the transient phase and highlight the importance of CSH‐CSSC interplay. Herein, it provides novel insights into molecular mechanisms governing active self‐assembly and offers strategies for designing tunable materials through controlled assembly conditions. 

Abstract The molecular basis underlying the rich phase behavior of globular proteins remains poorly understood. We use atomistic multiscale molecular simulations to model the solution‐state conformational dynamics and interprotein interactions of D‐crystallin and its P23T‐R36S mutant, which drastically limits the protein solubility, at both infinite dilution and at a concentration where the mutant fluid phase and crystalline phase coexist. We find that while the mutant conserves the protein fold, changes to the surface exposure of residues in the neighborhood of residue‐36 enhance protein–protein interactions and develop specific protein–protein contacts found in the protein crystal lattice.