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Well matched MRI-like Nuclear Magnetic Resonance (NMR) experiment (A) and Rosetta computer-generated (B) renditions of a protein’s structure. The Rosetta software can generate a protein structure, which could take several months to experimentally determine, in a few days and at a fraction of the cost. Credit: Srivatsan Raman, Harvard University 24 Protein Origami David Baker, Professor, University of Washington A human-generated folded protein from the online game Foldit. The idea of the game is to find out if the patternrecognition and puzzle-solving abilities of people make them more efficient than existing computer programs at some tasks involved in predicting protein structure. Such strategies might then be added to folding prediction software. Credit: David Baker, University of Washington The automatic prediction of a known protein structure (red) by the Robetta server overlaid on the native structure (blue). The agreement between both structures shows the atomic-level accuracy of Robetta’s predictions. Credit: Srivatsan Raman, Harvard University TeraGrid resources assist in the field of protein structure prediction, helping to decode illness and disease. I n the online game Foldit, human players, from high school students to retirees, are manipulating protein molecules as part of an effort to understand how proteins pack themselves into various shapes to perform the many functions they have in the body. Meanwhile, TeraGrid computational resources, and a TeraGrid Science Gateway called the Robetta Portal, are making it possible for thousands of researchers to look at the structures of thousands of proteins at once. These resources are helping move the field toward accurately predicting and designing protein structures and protein complexes, eventually with specific functions or disease targets in mind. Protein molecules are the workhorses of cells in all living things. They carry oxygen in the blood, break down glucose in the body to release energy, capture sunlight to feed growing plants, catalyze the chemical reaction that makes fireflies glow, and a lot more. Proteins also aid viruses in invading cells. AIDS can be tied to proteins that break through cellular defenses and replicate the HIV virus. Cancer is linked to damage in proteins that inhibit uncontrolled cell growth. Alzheimer’s disease is believed to be related to malfunctioning proteins that are normally part of healthy brain cells. The duties proteins perform or do not perform are governed by the shapes into which the ribbon-like chains of up to 1,000 amino acids, basic building blocks of life, fold themselves. Protein folding should produce a protein’s most stable, functional structure, with some amino acids wrapped inside and others hanging outside, some pairs of amino acids near each other, others positioned far apart. “When proteins do not align correctly, sickness and sometimes death can occur,” says David Baker, a University of Washington biochemist. Both Foldit and Robetta stem from the Rosetta software developed by Professor Baker and colleagues. Rosetta is software for predicting and designing protein structures, and studying protein folding mechanisms and proteinprotein interactions. Robetta automates the prediction process in a server environment, in effect putting it online. How does Robetta work? If a sequence has similarities to a known protein structure, Robetta leverages that in modeling the structure of the subject protein. If a sequence does not resemble a known protein, the system applies a storehouse of knowledge about proteins and protein structure and builds a model of the subject protein’s structure from the ground up. Foldit also is rooted in Rosetta. The game is designed to find out if the pattern-recognition and puzzle-solving of people make them more efficient than existing computer programs at some tasks involved in predicting protein structure, strategies that might then be added to folding prediction software. Determining the three-dimensional shapes of proteins may ultimately lead to finding cures for major human diseases by manipulating proteins, or even designing new ones, to fight HIV, cancer, Alzheimer’s, or malaria, for example. The problem is computationally demanding, however. “There are a huge number of possible structures that a protein could have,” says Baker, who also is a Howard Hughes Medical Institute scientific investigator. He likened the task to searching a large planet full of hills and valleys for the planet’s low point. “In that case, it helps to have a lot of explorers in the field,” says Baker. Currently serving nearly 8,000 registered users, Robetta allows researchers worldwide to submit protein sequences for automated structural analysis. The TeraGrid spreads the work over a variety of computing systems, including powerful supercomputers. For instance, Robetta can now run up to 300 jobs simultaneously in a distributed computing system of nearly 30,000 processors that makes use of machines at TeraGrid partner, Purdue University and on other campuses. The Robetta project also has made use of TeraGrid resources at the San Diego Supercomputer Center and the National Center for Supercomputing Applications at the University of Illinois. In addition, the TeraGrid has made Robetta’s power more accessible to researchers through the Robetta Portal Science Gateway, a website that makes submission of sample protein sequences for analysis easier. “It was just a natural match,” says Nancy Wilkins-Diehr, TeraGrid Area Director for Science Gateways. “The portal gives everyone access to this very high-quality, award-winning code.” “Having access to the massive computing resources of the TeraGrid is revolutionizing the approaches that are open for protein structure prediction,” Baker says. Relevant links: Robetta Portal http://robetta.bakerlab.org/ Foldit http://fold.it/portal/ Purdue University: http://purdue.edu 25