New Argonne study may shed light on protein-drug interactions

Jan 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: Liquid helium offers a fascinating new way to make charged molecules

add to favorites email to friend print save as pdf

Related Stories

Hacker gets prison for cyberattack stealing $9.4M

2 hours ago

An Estonian man who pleaded guilty to orchestrating a 2008 cyberattack on a credit card processing company that enabled hackers to steal $9.4 million has been sentenced to 11 years in prison by a federal judge in Atlanta.

Remains of French ship being reassembled in Texas

2 hours ago

A frigate carrying French colonists to the New World that sank in a storm off the Texas coast more than 300 years ago is being reassembled into a display that archeologists hope will let people walk over ...

Icelandic volcano sits on massive magma hot spot

2 hours ago

Spectacular eruptions at Bárðarbunga volcano in central Iceland have been spewing lava continuously since Aug. 31. Massive amounts of erupting lava are connected to the destruction of supercontinents and ...

Magic Leap moves beyond older lines of VR

3 hours ago

Two messages from Magic Leap: Most of us know that a world with dragons and unicorns, elves and fairies is just a better world. The other message: Technology can be mindboggingly awesome. When the two ...

NBCUniversal settles with unpaid interns for $6.4M

3 hours ago

NBCUniversal will pay $6.4 million to settle a class action lawsuit brought by unpaid interns who worked on "Saturday Night Live" and other shows who claim they are owed wages, according to court documents.

Recommended for you

Amino acids key to new gold leaching process

Oct 24, 2014

Curtin University scientists have developed a gold and copper extraction process using an amino acid–hydrogen peroxide system, which could provide an environmentally friendly and cheaper alternative to ...

Researchers create designer 'barrel' proteins

Oct 23, 2014

Proteins are long linear molecules that fold up to form well-defined 3D shapes. These 3D molecular architectures are essential for biological functions such as the elasticity of skin, the digestion of food, ...

User comments : 0