Spider dragline silk combines high tensile strength with exceptional toughness, yet the molecular steps that transform soluble silk proteins into solid fibers have remained unclear. Now, researchers from King’s College London and San Diego State University report that specific interactions between the amino acids arginine and tyrosine play a central role in this transition, linking early-stage protein condensation to the ordered structures found in the final fiber.
In the study, the team shows that cation-π interactions between arginine and tyrosine residues act as molecular “stickers.” These interactions promote liquid–liquid phase separation (LLPS) in native spider silk proteins and persist as the material assembles into β-sheet–rich fibers that underpin silk’s mechanical performance.
Spider dragline silk proteins, known as spidroins, are stored at high concentration in the spider’s silk gland as a viscous liquid. When spinning begins, these proteins undergo phase separation and are drawn into fibers. While LLPS has been implicated in this process, the residue-specific chemistry connecting condensation to fiber formation has been difficult to resolve, particularly in native silk rather than recombinant models.
To address this, the researchers combined solution-state nuclear magnetic resonance (NMR) spectroscopy, dynamic nuclear polarization (DNP)-enhanced solid-state NMR, molecular dynamics simulations, and AI-based structural modeling using AlphaFold3. Solution NMR experiments showed that phosphate ions trigger LLPS in native silk without inducing widespread β-sheet formation, while revealing pronounced chemical shift changes and altered dynamics at arginine and tyrosine sites. Solid-state DNP-NMR then directly detected Arg-Tyr contacts in spun fibers, demonstrating that these interactions are retained in the solid material.
Computational simulations supported the experimental findings, showing that phosphate promotes Arg–Tyr interactions while weakening contacts between arginine and alanine-rich regions that later form β-sheets. AlphaFold3 models placed arginine residues at β-sheet interfaces, with tyrosine often adopting turn-like conformations near these boundaries.
Chris Lorenz, Professor of Computational Materials Science at King’s College London, emphasized the broader relevance of the work in a press release: “The potential applications are vast – lightweight protective clothing, airplane components, biodegradable medical implants, and even soft robotics could benefit from fibres engineered using these natural principles.”
Gregory Holland, Professor of Physical and Analytical Chemistry at SDSU, highlighted the chemical sophistication involved: “What surprised us was that silk – something we usually think of as a beautifully simple natural fiber – actually relies on a very sophisticated molecular trick.” He also noted that similar interactions appear in biological signaling systems, adding: “The way silk proteins undergo phase separation and then form β-sheet-rich structures mirrors mechanisms we see in neurodegenerative diseases such as Alzheimer’s.”
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