New Argonne study may shed light on protein-drug interactions

January 15, 2008

Proteins, the biological molecules involved in virtually every action of every organism, may themselves move in surprising ways, according to a recent study from the U.S. Department of Energy’s Argonne National Laboratory that may shed new light on how proteins interact with drugs and other small molecules.

While scientists had expected proteins to behave similarly in regions of high and low protein concentration – from as high as 30 percent protein to less than one percent protein, respectively – they instead found that proteins had a much larger range of motion and could contort themselves into many more configurations in the dilute solutions. “The difference is comparable to skipping through an open field or being crammed into a crowded elevator,” said Argonne biochemist Lee Makowski, who headed the project.

This study represents a novel approach to characterizing the ways in which proteins move around in solution to interact with other molecules, including drugs, metabolites, or pieces of DNA, and relied on the intense x-ray beams available at Argonne’s Advanced Photon source.

The study of proteins had long focused almost exclusively on their structures, parts of which can resemble chains, sheets or helices. To determine these, scientists use high-energy X-rays to take snapshots of proteins frozen in a single conformation within a highly ordered crystal. However, biologists had made relatively little progress in using these pictures to show how proteins can reconfigure themselves in different environments.

“Proteins are not static, they’re dynamic,” Makowski said. “Part of the common conception of proteins as rigid bodies comes from the fact that we know huge amounts about protein structures but much less about how they move.”

For over a century, the standard model of protein behavior depicted them as inflexible “locks” that could interact only with a small set of equally rigid molecular “keys.” Even today’s introductory biology courses rely on descriptions of protein behavior that require them to swivel and pivot very little as they interact with other biological molecules, according to Makowski. “That’s a very powerful image but it’s not the whole story,” he said. “We’ve learned that proteins in solution can take on an entire ensemble of slightly different structures, and that, for most proteins, this ensemble grows much larger as you go to smaller and smaller concentrations.”

Makowski and his colleagues were also surprised to discover that environmental conditions strongly influence which state in this “ensemble” of conformations a protein prefers to enter. Most of a protein’s common configurations have a functional purpose, he said, as it is “not likely to twist itself into something completely irrelevant to its function.”

For example, one of the five proteins examined in the study, hemoglobin, has two favored conformations: one in which it binds oxygen very readily and one in which it does not. When hemoglobin is placed in a solution that contains a great deal of available oxygen, it spends most of the time in the former state, while if oxygen is not available, it usually flips into the latter. “We now know that in dilute solutions, hemoglobin actually can take on both conformations - even in the absence of oxygen,” he said.

By keeping all of the environmental factors the same save for the protein concentration in the solution, Makowski and his team discovered another surprising result. Scientists had known for many years that when proteins are too concentrated, they aggregate and fall out of solution. However, biochemists previously had difficulty explaining why a similar effect also occurs in overly dilute solutions.

Proteins have hydrophobic – or “water-hating” – core regions that try to avoid touching water if at all possible. Because of this characteristic, proteins will rearrange themselves to protect these regions from coming into contact with water. In dilute solutions, however, Makowski’s team discovered that proteins fluctuate far more than in concentrated solutions, and
these fluctuations expose the hydrophobic core of the proteins, making them more likely to stick to one another or to the walls of the container.

Source: Argonne National Laboratory

Explore further: Why bacteria could be the answer to a future without oil

Related Stories

Why bacteria could be the answer to a future without oil

July 30, 2015

Chemicals are all around us. They are crucial in all manner of industries, from agriculture to food to cosmetics. Most people give little thought to how these chemicals are made – and certainly very few would consider the ...

Yarn from slaughterhouse waste

July 29, 2015

ETH researchers have developed a yarn from ordinary gelatine that has good qualities similar to those of merino wool fibers. Now they are working on making the yarn even more water resistant.

Bleach a possible key to life on earth

July 23, 2015

Hydrogen peroxide - commonly used as hair bleach - may have provided the energy source for the development of life on Earth, two applied mathematicians have found.

The light of fireflies for medical diagnostics

July 22, 2015

In biology and medicine, we often need to detect biological molecules. For example, in cancer diagnostics, doctors need quick and reliable ways of knowing if tumor cells are present in the patient's body. Although such detection ...

Recommended for you

Study calculates the speed of ice formation

August 3, 2015

Researchers at Princeton University have for the first time directly calculated the rate at which water crystallizes into ice in a realistic computer model of water molecules. The simulations, which were carried out on supercomputers, ...

Small tilt in magnets makes them viable memory chips

August 3, 2015

University of California, Berkeley, researchers have discovered a new way to switch the polarization of nanomagnets, paving the way for high-density storage to move from hard disks onto integrated circuits.

4 million years at Africa's salad bar

August 3, 2015

As grasses grew more common in Africa, most major mammal groups tried grazing on them at times during the past 4 million years, but some of the animals went extinct or switched back to browsing on trees and shrubs, according ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.