Cutting through the Protein Knots
Now, for the first time, a distributed computing experiment has produced significant results that have been published in a scientific journal. Writing in the advanced online edition of Nature magazine, Stanford University scientists Christopher D. Snow and Vijay S. Pande describe how they -- with the help of 30,000 personal computers -- successfully simulated part of the complex folding process that a typical protein molecule undergoes to achieve its unique, three-dimensional shape.
Their findings were confirmed in the laboratory of Houbi Nguyen and Martin Gruebele, scientists from the University of Illinois at Urbana-Champaign who co-authored the Nature study.
Understanding molecular knots of life
Every protein molecule consists of a chain of amino acids that must assume a specific three-dimensional shape to function normally.
"The process of protein folding remains a mystery," said Pande, assistant professor of chemistry and of structural biology at Stanford. "When proteins misfold, they sometimes clump together, forming aggregates in the brain that have been observed in patients with Alzheimer's, Parkinson's and other diseases."
"One reason that protein folding is so difficult to simulate is that it occurs amazingly fast," Pande explained. "Small proteins have been shown to fold in a timescale of microseconds [millionths of a second], but it takes the average computer one day just to do a one-nanosecond [billionth-of-a-second] folding simulation."
Simulating protein folding is often considered a "holy grail" of computational biology, he added. "This is an area of hot competition that includes a number of heavyweights, such as IBM's $100 million, million-processor Blue Gene supercomputer project."
The Stanford project operates on principles similar to earlier projects, such as SETI@home, which allows anyone with an Internet connection to search for intelligent life in the universe by downloading special data-analysis software. When a SETI@home screensaver is activated, the PC begins processing packets of radio telescope data. Completed packets are sent back to a central computer, and new ones are assigned automatically. Soon to be announced versions will not just enable screensavers, but also work on browser toolbars (see Google Compute) to extend further the project's compass.
For the Nature study, Pande and Snow, a biophysics graduate student, asked volunteer PCs to resolve the folding dynamics of two mutant forms of a tiny protein called BBA5. BBA5 is a small protein with 23 amino acids with a well-known folded state. Each computer was assigned a specific simulation pattern based on its speed.
With 30,000 computers at their disposal, Pande and Snow were able to perform 32,500 folding simulations and accumulate 700 microseconds of folding data. These simulations tested the folding rate of the protein on a 5-, 10- and 20-nanosecond timescale under different temperatures. Using these data, the scientists were able to predict the folding rate and trajectory of the "average" molecule.
To confirm their predictions, the Stanford team asked Gruebele and Nguyen to conduct "laser temperature-jump experiments" at their Illinois lab. In this technique, an unfolded protein is pulsed with a laser, which heats the molecule just enough to cause it to bend into its native state. A fluorescent amino acid imbedded inside the molecule grows dimmer as the protein folds. Researchers use the changing fluorescence to measure folding events as they occur.
"These experiments represent a great success for distributed computing," Pande said. "Understanding how proteins fold will likely have a great impact on understanding a wide range of diseases."
The Stanford project continues to enlarge the size and complexity of folding projects, as more computer time and users are made available beyond the 200,000+ machines already available. As part of the interplay between theory and experiment, laboratory biologists are also seeking more information about basic protein design.
The European Space Agency's Granada Crystal Box Experiment, now aboard the International Space Station, is a small experiment designed to do big things in understanding proteins. The experiment, contained in a box only 13 x 13 x 8 cm, (5 x 5 x 3 inches) is intended to help answer questions about the structure of proteins.
In order to uncover the 3-D structure of proteins, scientists use X-ray crystallography, a method that requires the use of protein crystals, which are difficult to obtain on Earth. The Granada Crystal Box Experiment uses a new technique of growing protein crystals in microgravity (weightlessness). On Earth, gravity can hinder crystal formation. Researchers hope that by growing protein crystals in space they can obtain larger crystals with fewer imperfections, aiding in the analysis of proteins. Understanding how molecules organize into living systems is a major goal of astrobiology.
The Nature study was supported by the National Institutes of Health, the American Chemical Society, Intel and the Howard Hughes Medical Institute. The study, Absolute comparison of simulated and experimental protein-folding dynamics," is available online at www.nature.com.