Proteins are far more active and dynamic than scientists have imagined, say researchers at the University of Pennsylvania School of Medicine. Their study, to be published Thursday in the journal Nature, affords the first comprehensive view scientists have had of a protein’s internal motion. "The interior of a protein is much more liquid-like than scientists originally anticipated. Everything is moving, and it's moving all the time, very fast," said A. Joshua Wand, PhD, Professor of Biochemistry and Biophysics at Penn and principal author of the study.
"The really exciting thing is they move so much that, potentially, it dramatically influences how they work," Wand said. "This is the beginning of a long new story that, fundamentally, will have a lot to do with understanding protein function."
Wand and his colleague used nuclear magnetic resonance (NMR) relaxation imaging to track the activity of the calmodulin-peptide protein complex across a spectrum of 13 temperature settings that ranged from 278 degrees Kelvin to 346 degrees Kelvin (from 15 degrees Celsius to 73 degrees Celsius). The NMR data demonstrate that a much larger range of internal motion is present in calmodulin than crystallographic studies -- the standard method of discerning protein properties -- have had the capacity to demonstrate.
"The beauty of this experimental study is that motion and temperature are inextricably linked, and by understanding how motion changes in response to temperature, you understand more about the motions themselves," said Andrew Lee, PhD, a researcher who worked on the study with Wand at Penn as a postdoctoral fellow before taking a faculty position at the University of North Carolina. He added: "The common thinking has been that the structure of proteins dictates their functions, and that each one has a different biochemical task. But they aren't static structures -- they fluctuate, and that these fluctuations are also critical for protein activity."
In their research, Wand and Lee found the calmodulin protein has three distinct bands (or preferred magnitudes) of motion on a subnanosecond time scale, a richness of variation that was not previously known. Further, when they compared those findings with existing data on other proteins that had been studied at single temperatures, Wand and Lee discovered the same spectrum of motion. This suggests that the range of motion is a general fundamental property of proteins.
According to Wand, the research findings also suggests an explanation for the "glass transition" characteristic of proteins -- the feature that makes proteins respond to heat in the same fashion as glass. (The onset of dynamics in the glass transition is often associated with the attainment of biological activity.)
"The key word is 'entropy' -- the ability to assume multiple states," Wand said. "For a long time, people assumed proteins didn't have significant entropy, so they discounted its potential functional role. In fact, proteins have a lot more ways to accomplish their functions than we realized. This dynamism has central significance for how proteins may work."
"People tend to think of proteins as static, because they see pictures of them as snapshots. But now scientists will have to start considering the effects of entropy and dynamics," Lee added.
The new, more dynamic picture of proteins also offers a new direction for pharmaceutical companies that may eventually enable them to enhance the effectiveness of drugs by targeting more accessible protein sites, Wand said.
The research was funded by the National Institutes of Health.
The above post is reprinted from materials provided by University Of Pennsylvania Medical Center. Note: Content may be edited for style and length.
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