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| Water molecules are a driving force in the formation of molecular bonds, such as in proteins. Image Credit: INT, KIT |
Water is everywhere – it covers most of the earth, circulates in the human body and can be found in even the smallest molecular niches. But what happens if water does not flow freely but is trapped in such structures? Researchers at the Karlsruhe Institute of Technology (KIT) and Constructor University in Bremen have proven for the first time that "locked" water can influence its environment and strengthen the bond between molecules. This finding could open new avenues for the development of drugs and materials.
Some of the water on Earth is found in tiny nooks and crannies – enclosed in molecular pockets, such as protein binding sites or synthetic receptors. Whether this water behaves neutrally in the presence of other molecules or influences their binding has so far been controversial. "Water molecules usually interact most strongly with each other. However, experimental data showed that water behaves unusually in such narrow pockets", says Dr. Frank Biedermann from KIT's Institute of Nanotechnology. "We have now been able to provide the theoretical basis for these observations and prove that the water in the molecular pockets is energetically tense."
The researchers call this state "high energy"– not because the water glows or bubbles, but because it is in a higher energy state than ordinary water, namely, high energy water behaves like people in a crowded elevator: as soon as the door opens, they push out. Likewise, high-energy water pushes out of the molecular pocket when another molecule enters. It pushes the newcomer to the vacant place. The energy of the water thus strengthens the bond between the new molecule and the molecular pocket.
Results provide a prediction of the binding force
The researchers used the host molecule cucurbit [8] uril as the basis for their study. This can receive other molecules, also called guest molecules, and due to its high symmetry, it is much easier to analyze than very complex systems such as proteins. "Depending on the guest molecule, we were able to use computer models to calculate how much additional binding force the high-energy water provides", explains Professor Werner Nau from Constructor University in Bremen. "We found: the more energetically tense the water is, the more it supports the bond between the guest molecule and the host as it emerges."
Biedermann adds: "The data obtained clearly show that the concept of high-energy water molecules is physically based – and that these water molecules in particular represent a central driving force in the formation of molecular bonds. Even natural antibodies, such as those against SARS-CoV-2, may owe their effectiveness in part to the way they move water molecules in and out of their binding pockets."
Can be used for medicines or new materials
The findings of Biedermann and Nau could have a significant influence on medicine and materials science. In drug discovery, the identification of high-energy water in target proteins opens up the possibility of specifically designing active ingredients to displace this water, use its binding power and thereby become more stably anchored in the protein – which can improve the effectiveness of the drug. In materials science, creating cavities that exclude or displace such water could improve sensing or storage performance.
For their study, the researchers combined high-precision calorimetry – a method for measuring the heat released or absorbed during molecular processes – with computer models developed by Dr. Jeffry Setiadi and Professor Michael K. Gilson at the University of California, San Diego.
Authors: Dr. Jeffry Setiadi, Priv.-Doz. Dr. Frank Biedermann, Prof. Dr. Werner M. Nau, and Prof. Dr. Michael K. Gilson
Source/Credit: Karlsruhe Institute of Technology
Reference Number: chm101425_02