Metal-dependent and metal-free mechanisms of peptide condensate catalysts.
Peptide condensates just got more interesting. A new study in Nature Communications shows that minimal histidine-containing peptides, when packed together via liquid-liquid phase separation (LLPS), can catalyze reactions through two completely different routes—one with metals, one without.
Nat Commun
by Massarano T, Yang Y, Baruch Leshem A et al.
“Metal-dependent and metal-free mechanisms of peptide condensate catalysts. Massarano T(#)(1), Yang Y(#)(2)(3)(4)(5)(6), Baruch Leshem A(1), Eran O(1), Wang X(2)(3)(4)(5)(6), Dong H(7)(8)(9)(10)(11), Lampel A(12)(13)(14)(15). Author information: (1)Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel. (2)State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China. (3)Kuang Yaming Honors School, Nanjing University, Nanjing, China. (4)Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. (5)ChemBioMed Interdisciplinary Research Center, Nanjing University, Nanjing, China. (6)Institute for Brain Sciences, Nanjing University, Nanjing, China. (7)State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China. donghao@nju.edu.cn. (8)Kuang Yaming Honors School, Nanjing University, Nanjing, China. donghao@nju.edu.cn. (9)Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, China. donghao@nju.edu.cn. (10)ChemBioMed Interdisciplinary Research Center, Nanjing University, Nanjing, China. donghao@nju.edu.cn. (11)Institute for Brain Sciences, Nanjing University, Nanjing, China. donghao@nju.edu.cn. (12)Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel. ayalalampel@tauex.tau.ac.il. (13)Center for Nanoscience and Nanotechnology, Tel Aviv University, Tel Aviv, Israel. ayalalampel@tauex.tau.ac.il. (14)Center for the Physics and Chemistry of Living Systems, Tel Aviv University, Tel Aviv, Israel. ayalalampel@tauex.tau.ac.il. (15)Leibniz Institute of Polymer Research Dresden Max Bergmann Center of Biomaterials Dresden, Dresden, Germany. ayalalampel@tauex.tau.ac.il. (#)Contributed equally Condensates formed via liquid-liquid phase separation (LLPS) provide a chemically versatile environment for catalysis through dynamic molecular interactions. We present designed biomolecular condensates, formed by LLPS of minimalistic histidine-containing peptides, catalyzing ester hydrolysis with two distinct mechanisms. Zn2+-dependent condensates activate a coordinating water molecule at the active site, formed by Zn2+-histidine coordination, enabling nucleophilic attack. We show that dense-phase basicity, internal mobility, and Zn2+ accumulation within the condensates collectively govern their catalytic activity. In the absence of Zn2+, catalysis is driven by intermolecular low-barrier hydrogen bonds between histidine residues, facilitating nucleophile formation. Combined computational and experimental evidence reveals the molecular basis of these catalytic pathways, demonstrating the functionality of biomolecular condensates in catalysis and nanotechnology. These findings establish a foundation for exploring mechanisms of metal-free emergent catalysis within complex liquid assemblies, expanding the potential of LLPS-based systems in green chemistry and advanced materials. © 2026. The Author(s). Conflict of interest statement: Competing interests: The authors declare no competing interests.”
The researchers built peptide condensates that either included zinc ions (Zn2+) or didn’t. In the Zn2+-dependent setup, zinc locks in with histidine, grabbing water molecules and boosting ester hydrolysis. The whole process hinges on how Zn2+ sits inside the dense condensate, how basic the environment is, and how freely molecules can move around inside. That’s a recipe for fine-tuning catalytic activity.
But here’s the kicker: even with no metal around, these same peptide assemblies get the job done. Instead of metal magic, it’s all about low-barrier hydrogen bonds between histidines. These bonds help whip up nucleophiles, pushing the reaction forward. Computational models and lab experiments both back up these dual roles—metal-powered and metal-free.
Why does this matter?
LLPS-driven peptide condensates open new doors for designing catalysts that don’t need traditional enzymes or bulky proteins.
Metal-free catalysis by peptides is a big deal for green chemistry: fewer reagents, simpler systems.
This dual mechanism concept could spill over into nanotech and advanced material science.
Key takeaway: peptide assemblies aren’t just passive clumps—they can actively drive chemical reactions, with or without metal help. LLPS-based systems are positioned to become workhorses for sustainable catalysis and innovative biomaterials. There’s a lot more to explore, but the foundation is set.
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