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Feeling the Heat Two interacting proteins move differently as they heat up. Computer simulations have shown that each pair of proteins bound to each other undergo a profound change in their relative motion as they heat up, a phenomenon that could provide clues to how proteins interact to govern living cells.
The molecular dynamics simulations of protein interactions, product of an international collaboration led by ORNL researcher Jeremy Smith, are being run on the Cray XT4 Jaguar supercomputer in Oak Ridge. The simulations set the stage for neutron scattering experiments to test the theory by measuring the motion of proteins, the worker molecules of life. Smith, who leads the ORNL Center for Molecular Biophysics and holds a University of Tennessee—ORNL Governor's Chair, collaborated with researchers from the University of Heidelberg in Germany. Their study appeared in the April 1, 2008 edition of Physical Review Letters. "The living cell is a network of proteins that talk to each other by interacting, sometimes transiently, sometimes for long periods of time," Smith says. "These interactions are important at every stage of cell function. Understanding the physical nature of these associations will help us comprehend why they form and when." The simulations performed by his team followed the way a pair of interacting proteins moves relative to each other as temperature increases. Internal motions in proteins and many other materials undergo a rapid softening at a certain temperature, a phenomenon called the "glass-to-liquid," or simply "glass" transition. The new simulations show that a glass transition also is evident in the way proteins in a pair, or "complex," move relative to each other. At very low temperatures, around -200°C, protein complexes are frozen stiff in a glassy state. At around -40°C, they suddenly free themselves up and behave like molecules in a liquid, diffusing randomly relative to each other, while still remaining in touch. "The effect is a bit like a couple dancing for the first time together at a ball," Smith says. "In the beginning, at low temperatures they just rigidly and uncomfortably hold each other, but after a while, as the temperature rises, they get used to each other and move more fluidly, with more adventurous motions, all while maintaining body and eye contact." The motion may in the future become measurable using specialized spectrometers at the Spallation Neutron Source, as neutron scattering has historically been a major technique for examining glass transition behavior. "The importance of neutrons stems from their unique capability of allowing the direct measurement of both where atoms move and how fast they get there—in other words, both the geometries and time scales of motions," he says. Exactly how protein pairs dance together in a living cell is yet to be determined. Maybe, as in the glass transition behavior, they mimic what happens inside proteins themselves. In a new theoretical article by Smith, also due to appear in Physical Review Letters, he demonstrates that the internal motions in a protein are likely to obey "anomalous subdiffusion" on a "fractal network." In other words, the motion is more complex than usual as it follows a specific geometrical form. "Possibly the relative motions of proteins in a living cell will follow similar rules," Smith says. "To find out whether this is the case, our team is wasting no time pushing forward with a massive simulation of 3.5 million atoms in a thousand interacting proteins, running on the ORNL Cray XT4 Jaguar supercomputer. This high-performance simulation will stretch the capability of Jaguar but, if successful, will be a rich source of information, helping us to understand the forces between proteins."—Bill Cabage
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