Water molecules and proteins make good dance partners, and LAS scientists have the evidence to back it up.
An LAS research team has become the first to measure the activity of water molecules as they perform an intricate ballet during protein folding, a process that enables proteins to perform their jobs within the body. Water molecules are not idle spectators to the folding process, but are part of a delicate dance essential to life.
“Scientists usually watch the protein when they study protein folding. But we watched the surrounding water molecules,” says Martin Gruebele, a University of Illinois chemist who collaborated on the research with Martina Havenith at Germany’s Ruhr-University Bochum.
“Our body is made up of 70 percent water, but water in the human body doesn’t behave like the bulk water we’re accustomed to,” Gruebele says. Surrounded by proteins, organelles, mitochondria, cell membranes, and other microscopic matter, water in the body can act in very different ways, influencing such processes as protein folding.
He likens protein folding to taking a long string of yarn and packing it together into a ball—except that proteins must fold in very specific ways. During this process, proteins can dramatically affect the motion of surrounding water molecules as they dance on the surface of the protein. They can slow down the water molecules and sometimes make them spin more easily.
In turn, water molecules can affect proteins. “It’s a two-way street,” Gruebele says. For instance, water molecules can slow down the process of protein folding, staving off such problems as Alzheimer’s disease. If a protein folds too quickly, that means it also runs the risk of unfolding too easily. When proteins unfold in the brain, they can clump together as plaque, causing the death of neurons. The result can be Alzheimer’s.
Understanding how water molecules and proteins interact also has implications for pharmaceuticals, which are often used to block certain proteins, he adds. The water molecules around proteins in the body can affect how drugs bind to proteins, preventing them from working as intended.
“So drug makers are looking for answers that tell them what the water does,” Gruebele says.
In the joint U of I/Germanyy study, researchers observed how water molecules dance with ubiquitin, one of the body’s most prevalent proteins. Gruebele says they observed that the water molecules moved into a native configuration in milliseconds, before the ubiquitin protein folded into its native shape—suggesting a possible influence on the folding process.
“I can’t completely guarantee that there is a cause and effect relationship based on one protein we studied, but it’s possible that water molecules play a substantial role,” he notes. “To confirm, we need to do more experiments on different proteins.”
What’s clear at this point, however, is that the water molecules do contribute roughly half of the energy to the protein folding process.
To follow the water-protein ballet in time, Gruebele’s team used terahertz absorption spectroscopy, which emits ultra-short laser pulses. He says researchers in California used the same technique several years ago, but they had to use a free electron laser that took up an entire building, and very high sample concentrations were needed to see any signal. The U of I/Germany team was the first to use the system with biological molecules at low concentration, using a dramatically cheapern instrument that fit on top of a table and was dramatically cheaper.
To take the water-protein work a step further, researchers are going to use the same terahertz process to study antifreeze proteins, which strongly affect the structure of water molecules. These proteins, which are much more powerful than the antifreeze used in cars, enable fish to survive in Arctic waters without freezing. They prevent ice crystals from forming within water inside the fish’s body.
“Before now, people have not been able to study the antifreeze mechanism in detail because they didn’t have the tool to look at what the protein is actually doing to the water,” Gruebele says. “But now we can do that.”
By Doug Peterson — January 2009