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“Water is not just the backdrop of life’s chemistry—it often drives the action,” says Werner Nau, Professor of Chemistry at Constructor University and co-lead author of a new study in Angewandte Chemie International Edition. “By understanding how water molecules behave inside molecular binding sites, we can design stronger, smarter interactions for applications in fields from medicines to materials.”
Water is everywhere in life, covering most of our planet, making up the majority of our bodies, and forming the stage on which all biology plays out. Yet not all water behaves the same. Most is part of the vast, free-flowing ocean of bulk liquid, but some finds itself trapped in tiny nooks and crannies, confined inside molecular pockets such as protein binding sites or synthetic receptors. These trapped waters live under unusual rules, unable to make all their favorite hydrogen-bond connections. In effect, they’re like guests crammed into an overheated elevator: eager to get out if someone opens the door.
Scientists sometimes call this “high-energy water” — not because it glows or fizzes, but because it’s in a less comfortable, more energetic state than ordinary water. Displacing such water when another molecule moves in can give a surprising “boost” to the strength of the interaction, almost as if the water itself is helping to push the newcomer into place.
This is exactly what Werner Nau and Frank Biedermann of the Karlsruhe Institute of Technology (KIT) have first measured and now mapped. Their study shows, in quantitative detail, how much extra “binding power” can come from evicting high-energy water. The work focuses on model host–guest systems, molecular containers that mimic the way biological pockets hold onto molecules, allowing the team to tease apart the precise thermodynamic contributions of water displacement.
Quantifying the role of a few invisible water molecules is no simple task. The researchers initially used high-precision calorimetry, which measures the heat released or absorbed in molecular events, but the full picture could only be resolved with the computational modeling performed by Jeffry Setiadi and Michael Gilson at the University of California San Diego. Together, they could assign numbers to the “free-energy bonus” that comes from removing high-energy water.
One striking example came from the macrocyclic molecule cucurbit[8]uril, a widely studied molecular host. When it binds a guest, the departure of the encapsulated water molecules delivers an especially large thermodynamic payoff. The team’s results put hard data behind a principle long suspected but rarely proven: the more uncomfortable the water, the more it helps when it leaves.
This insight has far-reaching implications. In drug design, identifying high-energy waters in a protein target could help chemists design molecules that push them out, improving potency and specificity. In materials science, crafting cavities that exclude or eject such waters could enhance sensing or storage performance. Even nature’s enzymes may owe part of their efficiency to how they marshal water molecules in and out of their active sites.
“High-energy water has been part of the conversation in supramolecular and biomolecular chemistry, but the numbers were hard to pin down,” says Prof. Biedermann. “Our results provide a quantitative map that chemists and biochemists can apply across different systems to anticipate how water will influence binding.”
The work is a German American collaboration between Constructor University, KIT, and UC San Diego, and was selected for the Front Cover of Angewandte Chemie — a mark of its wide scientific interest.
The study, “Thermodynamics of Water Displacement from Binding Sites and its Contributions to Supramolecular and Biomolecular Affinity,” appears in Angewandte Chemie International Edition (2025), DOI: 10.1002/anie.202505713.
Prof. Dr. Werner Nau, Professor of Chemistry, Constructor University
wnau@constructor.university
Right in his element: Constructor University chemistry professor Dr. Werner Nau
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Right in his element: Constructor University chemistry professor Dr. Werner Nau
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