The Computational Microscope Ranger’s power enables Klaus Schulten to model the largest biomolecular ap- paratus to date

In the 300 years since Dutch scientist, Antonie van research, Schulten’s molecular simulations are open- Leeuwenhoek, first discovered living cells with his ing new realms of research that help us understand homemade lenses in 1674, microscopes have grown fundamental aspects of how life exists on earth. hundreds of thousands of times more powerful. Em- ploying new methods and techniques, from electron Schulten uses a football game as an analogy to explain beams and atomic probes to x-rays, the frontier of how the computational microscope combines diverse magnification has moved from the cell to the mol- microscopy techniques. “Crystallography,” Schulten ecule, trillions of which work in tandem to create life. said, “is like football players listening to the national anthem before the game. They stand there, and if you “All life forms are actually a society of molecules, a take a good photograph, you can see them all pre- very hierarchical society,” Klaus Schulten, preeminent cisely.” molecular biologist and professor of at The University of at Urbana-Champaign, ex- plained. “But we’re also more than molecules. Water is made of molecules, but it cannot repair or duplicate itself. The point about molecules in living systems is they form teams and work together.”

To truly understand the human body, and to design effective medicines and treatments, it is necessary to grasp the operations of cellular molecules from the atomic level up. While the functions of biomolecules, like proteins and DNA, are well known, certain aspects of the proteins’ actions elude researchers — even when using the most powerful microscopes.

Schulten has spent his career extending the limits of microscopy by applying the immense power of Shown here is a schematic drawing of a chromatophore from Rb. to molecular imagery. His “computa- sphaeroides. The LH1-RC dimers and LH2 complexes are closely tional microscope” takes information from laboratory packed in the bulb of the chromatophore, as seen in AFM images, tests and turns it into dynamic, three-dimensional and the bc1 complex and ATP synthase, which are absent from AFM images, are tentatively placed near the neck of the chromatophore. images with a powerful program Schulten created called NAMD (NAnoscale , pronounced “NAM-dee”). Joining electron micros- But during the game, the players (molecules) are in copy, x-ray crystallography, quantum chemistry and motion, interacting, bumping into one another, which multi-scale molecular dynamics, with the massive is where electron microscopy plays a role. “Here, parallel processing power of Ranger, the most pow- you can capture the biomolecules in action, but not erful in the world for open science with the same resolution as in the crystal,” Schulten

For more information, please contact: Faith Singer-Villalobos, Public Relations, [email protected], 512.232.5771 Page 1 of 4 The Computational Microscope explained. “You don’t see every detail, but you see ribosome, modeling three million atoms and discover- enough that you can match the straight standing play- ing new facets of this essential protein factory. ers to the actors on the field and learn what are they doing — where are their legs? where are their heads? In the coming months, working with experimentalists, do they have the football?” computational scientists, and other theorists, Schulten will use Ranger to model the largest and most com- Combining these two methods tells you what you’re plex biomolecular machinery to date: the 100 million looking at from the outside. But to see the molecule atom chromatophores of purple bacteria. from the inside out and to understand how it forms and what it does, you need an all-atom representation of the protein. “Only when you know the chemical detail can you make sense of what is actually happen- ing,” Schulten said. “In football language, who has the ball? who kicks the ball? who throws the ball? You can reconstruct this detail through the application of the computational microscope.”

Ranger, the newly launched supercomputer at the Texas Advanced Computing Center (TACC), will integrate the data from these varied methods on thousands of parallel processors, and output movies of the molecular machinery in motion. These informa- tion-rich visualizations, in turn, will help fuel the next round of molecular dynamics breakthroughs.

Coming from Schulten, it sounds simple, but in reality, this process is the product of more than two decades of coding and refinement, and $20 million in funding from the National Institute of Health (NIH). Today, Schulten’s parallel molecular dynamics pro- gram, NAMD, is the leader for large-scale simulations of biomolecular systems (more than 100,000 atoms) and one of the most capable parallel scientific codes ever run on a supercomputer. Simulation of the LH1-RC-PufX dimer. LH1 is colored in blue, the RCs in green, and PufX in red. a) Snapshots at the beginning of the simulation, viewed from the cytoplasm (top), and in the plane of the Schulten has used NAMD to do some of the most membrane (bottom). b) Snapshot of the simulated system at the end intensive molecular dynamics simulations ever at- of the 20 ns equilibration. The LH1 protein exhibits a slight bending towards the periplasmic side. The membrane adapts to the LH1’s tempted. His 2006 simulation of the satellite tobacco change in shape. mosaic was the first to capture a whole biologi- cal organism in intricate detail. It showed the million- (This image was made with VMD and is owned by the Theoretical and Computational Group, an NIH Resource for Macro- atom virus pulsing in a solution of water as if it were molecular Modeling and Bioinformatics, at the Beckman Institute, breathing. In 2007, he simulated the actions of the University of Illinois at Urbana-Champaign)

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“Organelles like the chromatophore are like the or- the computer can do,” Schulten said. “With their gans in the body — small but important parts of the research, you recognize only the rough shape of the cell that have distinct functions,” Schulten said. “In membrane, whereas we see every one of its atoms.” the case of the chromatophore, the function is absorb- ing sunlight and turning it into chemical fuel that the The formation of protein domes is just one process in cell needs for many of its processes.” living cells that will be explored by Schulten and his team on Ranger in the next few years. Additional sim- For decades, Schulten had studied the parts of the ulations will show the functioning of all the proteins chromatophore one-by-one. “What Ranger will per- active in the chromatophore. And Schulten is only one mit us to do, on a much larger scale than ever before, of thousands of researchers who are using NAMD is look at the concerted activity of the molecules in the to uncover insights about the molecular machinery, chromatophore, not just one at a time, but at many of providing an incredible multiplier for the field. them.” Perhaps as importantly, Schulten’s experience using One of the first questions that Schulten’s research his highly-scalable NAMD code on Ranger points the explores is what gives the chromatophore its spheri- way to future algorithms and scalable codes capable cal shape? Or, as Schulten puts it: “How do cells of modeling larger and larger molecules on next-gen- build their own houses?” Using Ranger, Schulten eration high-performance computing systems. simulated the most common chromatophore protein interacting with the cell membrane. He found that if “We can already see on the horizon that what we the proteins are put on a flat membrane, they dome are doing on Ranger today will be done in the office the membrane, form a spherical bubble, and then cut tomorrow,” Schulten said. “Someone has to begin to themselves off. use these kinds of machines with many processors to teach the world how to use them effectively, to de- “We did test calculations to get a sample. Then, to be velop new algorithms that work with parallel proces- sure of how these proteins are arranged in the mem- sors, so they could be used effectively tomorrow by brane — how tightly packed they are — we did all everybody.” kinds of varieties of simulations, just as in the lab you do all kinds of experiments,” Schulten said. “In the Unraveling the mysteries of life with the help of a old days, you were happy if you could do one sample computational microscope, Schulten’s research is one calculation. But with Ranger, we can do several of more reason to stay tuned to TACC and Ranger for them to be sure that we’re not being led astray.” world-changing scientific discoveries.

The day Schulten and his colleagues submitted their ### computational study[1] of domed chromatophore proteins, researchers from Harvard University an- The Ranger supercomputer is funded through the National nounced that they had shown experimentally that Science Foundation (NSF) Office of Cyberinfrastructure other proteins were curving a different cellular mem- “Path to Petascale” program. The system is a collaboration brane, the endoplasmic reticulum, in a similar man- among the Texas Advanced Computing Center, The Uni- ner. “They are showing experimental views of this versity of Texas at Austin’s Institute for Computational phenomenon at a much lower resolution than what Engineering and Science, Sun Microsystems, Advanced

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Micro Devices, Arizona State University, and Cornell University.

Ranger is a key resource of the NSF TeraGrid (www teragrid.org), a nationwide network of people, resources and services, also sponsored by the NSF Office of Cyberin- frastructure, which enables discovery in U.S. science and engineering. The TeraGrid provides scientists and research- ers expertise in and access to large-scale computing power, networking, data-analysis, and visualization systems.

Aaron Dubrow Texas Advanced Computing Center Science and Technology Writer April 2008

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