Measuring the unseeable: Researchers probe proteins' 'dark energy'

Jul 19, 2007
Penn Researchers Probe Proteins
Artist rendering of calmodulin molecule depicting protein 'dark energy.' Credit: Mary Leonard and Michael Marlow, PhD, University of Pennsylvania School of Medicine

Researchers at the University of Pennsylvania School of Medicine are the first to observe and measure the internal motion inside proteins, or its “dark energy.” This research, appearing in the current issue of Nature has revealed how the internal motion of proteins affects their function and overturns the standard view of protein structure-function relationships, suggesting why rational drug design has been so difficult.

The situation is akin to the discussion in astrophysics in which theoreticians predict that there is dark matter, or energy, that no one has yet seen,” says senior author A. Joshua Wand, PhD, Benjamin Rush Professor of Biochemistry. “Biological theoreticians have been kicking around the idea that proteins have energy represented by internal motion, but no one can see it. We figured out how to see it and have begun to quantify the so-called ‘dark energy’ of proteins.”

Proteins are malleable in shape and internal structure, which enables them to twist and turn to bind with other proteins. “The motions that we are looking at are very small, but very fast, on the time scale of billions of movements per second,” explains Wand. “Proteins just twitch and shake.” The internal motion represents a type of energy called entropy.

Current models of protein structure and function used in research and drug design often do not account for their non-static nature. “The traditional model is almost a composite of all the different conformations a protein could take” says Wand.

The researchers measured a protein called calmodulin and its interactions with six other proteins when bound to a protein partner one at a time. These binding partners included proteins important in smooth muscle contraction and a variety of brain functions.

Using nuclear magnetic resonance spectroscopy, the investigators were able to look at the changes in the internal motion of calmodulin itself in each of the six different protein binding situations. They found a direct correlation between a change in calmodulin’s entropy –a component of its stored energy – and the total entropy change leading to the formation of the calmodulin-protein complex. Finding out the contribution from individual proteins versus the entropy, or movement, of the entire protein complex has been more difficult and has been overcome in this study. From this individual contribution they deduced that changes in the entropy of the protein are indeed important to the process of calmodulin binding its partners.

“Before these unexpected results, most researchers in our field would have predicted that entropy’s contribution to protein-protein interactions would be zero or negligible,” says Wand. “But now it’s clearly an important component of the total energy in protein binding.”

Because of this new information, the researchers suggest that the entropy component may explain why drug design fails more often than it works. Currently, drugs are designed generally based on the precise structures of their biological targets, active regions on proteins that are intended to inhibit key molecules. However, the number of designed molecules actually binding to their targets is low for many engineered molecules. “We think that this is because the design is based on a model of a static protein, not the moving, hyper protein that is constantly changing shape,” say Wand. “We need to figure out how this new information fits in and perhaps drug design could be significantly improved.”

Future directions include understanding whether the principles revealed by this study are universal and impact the thousands of protein-protein interactions that underlie biology and disease. As Wand explains, “Protein-protein interactions are central to ‘signalling’, which is often the molecular origin of diseases. Cancer, diabetes, and asthma are three important examples. We are currently looking at the role of protein entropy in the control of critical signaling events in all three.”

Source: University of Pennsylvania

Explore further: China bans ivory carving imports for one year

add to favorites email to friend print save as pdf

Related Stories

Combination of imaging methods improves diagnostics

Feb 19, 2015

Scientists from the Helmholtz Zentrum München and the Technische Universität München have succeeded in a breakthrough for the further development of contrast agents and consequently improved diagnostics with imaging using ...

Voltage tester for beating cardiac cells

Feb 17, 2015

For the first time, scientists have succeeded in recording the current in membrane channels of contracting cardiac cells. To do this, the scientists combined an atomic force microscope with a widely used ...

Worms in space: Exploring health effects of microgravity

Feb 10, 2015

Humans may inevitably explore other planets, moons, and asteroids within our solar system. And although life on Earth has adapted to our planet's gravitational field, this looming possibility begs the question: ...

Lab-on-a-chip to study single cells

Feb 13, 2015

Scientists at EPFL have developed a new lab-on-a-chip technique to analyze single cells from entire population. The new method, which uses beads and microfluidics can change the way we study mixed populations ...

Live bacterium depicted using X-ray laser

Feb 11, 2015

An international team led by Uppsala University scientists has succeeded, for the first time, in depicting intact live bacteria with an X-ray laser. This technique, now described in the journal Nature Co ...

Recommended for you

China bans ivory carving imports for one year

4 hours ago

Beijing has imposed a one-year ban on the import of ivory carvings, amid international criticism that rapidly-growing Chinese demand could push wild African elephants to extinction within a generation.

Living in the genetic comfort zone

12 hours ago

The information encoded in the DNA of an organism is not sufficient to determine the expression pattern of genes. This fact has been known even before the discovery of epigenetics, which refers to external ...

Cats put sight over smell in finding food

14 hours ago

Cats may prefer to use their eyes rather than follow their nose when it comes to finding the location of food, according to new research by leading animal behaviourists.

User comments : 0

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.