Hidden high-energy water reveals a new molecular force

A portion of Earth's water resides in extremely small spaces, including molecular cavities found in protein binding sites or synthetic receptors. Scientists have long debated whether water in these confined regions simply behaves as a passive bystander or affects how molecules interact. "Usually, water molecules interact most strongly with each other. However, data obtained from experiment shows that water behaves unusually in such narrow cavities," says Dr. Frank Biedermann of KIT's Institute of Nanotechnology. "We now could supply the theoretical basis of these observations and prove that the water in molecular cavities is energetically activated."

Why "Highly Energetic" Water Matters

The team describes this unusual state as "highly energetic." This does not mean the trapped water glows or fizzes. Instead, it holds more energy than ordinary water. A simple analogy is people packed into a crowded elevator: the moment the door opens, they hurry to escape. Similarly, highly energetic water rushes out of a cavity when another molecule arrives, giving that incoming molecule an open position. This release of water helps strengthen the bond between the newcomer and the molecular cavity.

Predicting How Strongly Molecules Will Bind

To explore this effect, the researchers used cucurbit[8]uril as a model "host" molecule. This structure can hold "guest" molecules, and because of its high symmetry, it is far easier to study than a complex protein. "Depending on the guest molecule, computer models enabled us to calculate how much more binding force the highly energetic water yields," explains Professor Werner Nau of Constructor University in Bremen. "We found that the more energetically activated the water is, the better it favors binding between the guest molecule and the host when it is displaced."

Biedermann continues: "The data obtained clearly shows that the concept of highly energetic water molecules is physically founded -- and that those very water molecules are a central driving force during the formation of molecular bonds. Even natural antibodies, for example against SARS-CoV-2, might owe their effectiveness partly to the way how they transport water molecules into and out of their binding cavities."

Potential Applications in Medicine and Materials Science

These findings may have important implications for drug development and advanced materials. In drug design, identifying highly energetic water inside target proteins could help chemists create molecules that intentionally push this water out, harness its energetic contribution, and anchor themselves more strongly to the protein -- ultimately improving drug effectiveness. In materials research, creating cavities that force out or displace such water could lead to better sensors or materials with improved storage capabilities.

To reach their conclusions, the research team paired high-precision calorimetry -- a technique used to measure heat changes during molecular interactions -- with computer models developed by Dr. Jeffry Setiadi and Professor Michael K. Gilson at the University of California in San Diego.