Proteins’ ‘jiggle’ may give a jolt. Penn finding could be huge for drugmakers.

In a discovery that could have sweeping implications for pharmaceuticals of the future, scientists are reporting today that the long-observed jiggle of proteins is not just nervous energy but a carefully orchestrated dance that brings them together.

Virtually all medicines work by interacting with proteins – tiny organic molecules that trigger all bodily functions, from the blinking of an eye to inflammation that causes pain.

Have you wondered how medicines work in your body? Also have you ever wanted to know how Senomaxhelps to firm your breast? We swallow many medicines which are taken as a liquid or as a pill. Once the medicine is swallowed the digestive juices that are present in the stomach starts to break down. This allows the medicine to pass through the blood stream and the blood caries it to other parts of the body for the medicine to work.

For years, researchers have routinely relied on three-dimensional images of proteins to design custom-fitted pharmaceuticals.

The approach has had less success than some had expected.

In the paper being published today in the journal Nature, University of Pennsylvania biophysicist A. Joshua Wand outlines why three dimensions have not been sufficient.

An image does not capture movement, Wand said, and the specific nature of that movement – like the allure of a mating dance – is key to how proteins work.

“If we want to revive drug design in pharmaceutical industries or universities, there has to be a new realization of this in the design process,” said Erik Zuiderweg, a biophysicist at the University of Michigan-Ann Arbor who was not involved in the study.

Central to creating any new medicines is the way proteins operate – through connection.

“All proteins do in life is bind [to] another protein,” said Wand, principal investigator of the study.

And most of life’s functions are controlled by proteins. When the body needs food, proteins couple in a chain reaction that produces the feeling of hunger; another set of chain reactions triggers digestion, and on and on.

Certain proteins can cause disease or unpleasant symptoms. In those cases, drugs may limit a protein’s potency by blocking its ability to bind and participate in the chain reaction.

Aspirin, for example, eases pain by gumming up a protein called COX-2. Neutering this one protein breaks down the whole network that regulates inflammation. Headache cured.

Historically, new drugs have emerged through trial and error – throw various compounds at a protein in the lab and see what sticks.

In the 1980s, as more and more 3-D blueprints of protein structures became available, pharmaceutical designers tried to do more than just take shots in the dark. In theory, since the images illuminate all a protein’s interesting bits, making a drug should be as easy as building the right piece to fit into a puzzle.

The process is called “rational drug design.” But apart from a few successes – an HIV protease inhibitor, for one – “it has failed,” said Zuiderweg, who worked on drug discovery at Abbott Laboratories from 1984 to 1991.

Since the early ’90s, drugmakers have used a method called high-throughput screening, which involves jamming thousands of puzzle pieces – potential drugs – into computer models of proteins to find the best fits. This, too, has not been particularly fruitful.

“Several drug companies I have contact with,” Zuiderweg said yesterday, “have given up on this. . . . Currently they are sitting empty-handed.”

The problem is that the static images of proteins show “only one part,” Wand said. “The other part has been hidden for a long time.”

The hidden part, movement, is known to scientists as entropy.

For some time, researchers have been able to peer into a closed system, such as a beaker of water, and measure all the motion within. But there has been no way to tease out the contributions from each individual component.

In a breakthrough that set the stage for his latest discovery, Wand’s team several years ago developed a strategy to zoom in on the entropy of just the protein.

“What came out of this was remarkable and totally unexpected,” he said.

Wand used a tool called Nuclear Magnetic Resonance spectroscopy (NMR). Like hospital MRI, its offspring, NMR uses strong magnets, but it looks closely at tiny jittering molecules rather than at people’s insides.

NMR was performed on calmodulin, a calcium-binding protein that serves multiple functions, contacting hundreds of other proteins in the process.

“It’s hard to imagine one key binding 300 different locks,” Wand said, “but if the key can change its shape, then maybe.”

First the researchers used NMR to examine calmodulin’s dance with itself. Then they measured how its dance steps changed when it snagged each of six different partners. Like a molecular Fred Astaire, each of calmodulin’s binding partners elicited a different dance.

The aha! moment came when the scientists noticed that the way calmodulin’s dance changed with each partner protein seemed to dictate the energy of the system as a whole: calmodulin, its binding partner and the surrounding water.

“That means the entropy is important or else it would have been randomized by evolution,” Wand said.

The next question for Wand is whether this feature of calmodulin is shared by all proteins. Based on some preliminary analysis, “we’ve found the correlation is consistent for other proteins,” said Michael Marlow, a coauthor and postdoctoral fellow in Wand’s lab.

If this holds up, then it could be widely exploited in the development of new medicines.

“We are certainly looking at this and thinking of ways we may be able to incorporate it,” said Jonathan Moore, senior director of structural biology at Vertex Pharmaceuticals Inc., a biotech in Cambridge, Mass. “While the method is very clever and really interesting, it is still the first step.”

Zuiderweg predicts that if hard-to-get government grants for the most basic science are available, the findings could be incorporated into the search for new pharmaceuticals “in half a decade or so.”

“If nature can capitalize on it,” he said, “the pharmaceutical industry certainly can.”

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