The Bytes Behind Biology

The Bytes Behind Biology BigBen's 21 cabinets hold 4,136 processors Performing 21 trillion calculations per second, a supercomputer in Pittsburgh provided the first atomic-level look at the inner workings of the nuclear pore complex. That's just one of its accomplishments. By Andrea Gawrylewski ARTICLE EXTRAS 1 Preexisting models, based on electron microscopy and experimental work, had suggested four calcium binding sites to facilitate neurotransmission. Stiles created a model of single calcium channels with stochastic opening and closing, which allowed him to watch the influx of calcium through single channels, trace each ion as it entered through each channel independently, and look at the vesicle it happened to bind to, if any. By varying the number of binding sites and relating that to the molecular data, all while tracking the release of neurotransmitter, the group came up with a different estimate of the number of binding sites. "It turns out that we find that we need many more than four biding sites for calcium," Stiles says. Otherwise, "the system is so insensitive that nothing would ever happen." Inside the computer, a cooling fan is more than a foot in diameter. © Mark Bolster Photography The model enables Stiles to change variables in the system, such as knocking out some calcium channels, which mimics what happens with certain neurodegenerative diseases. He can also stimulate the cell more than once in the simulation, releasing a stronger concentration of neurotransmitters and recreating both short-term and long-term plastic changes in the brain. "We're always driven by wanting to answer new scientific questions," Stiles says. "You have no choice in doing the software development alongside the application, and that is an enormous task." One of the pitfalls of the PSC research comes from believing it too much. It's a powerful tool that produces picture-perfect images, and the scientists must constantly remind themselves that what they see is a representation, not reality. "In our job we forget that we're looking at models, and need verification," says Stiles' coworker Troy Wymore. Computer-based researchers, he adds, must be careful not to say of their work: "This is nature." Indeed, glitches small and large pop up. Later in the day, Stiles hovers over a computer workstation for one of the NRBSC software developers, Jack Chang, who scoots on his rolling chair between two computer terminals. The program has hit a snag resulting from an upgrade in the operating system software, which has stalled the work. "It's just one of those silly problems with the operating system," Stiles reassures. "It's not minor," returns Chang, peering into the screen. His bright yellow t-shirt reads: "Supercomputing is our middle name." "I said silly, not minor." Stiles accepts these speed bumps as just part of the job. By the end of the day the glitch is resolved, and work proceeds. Two doors down from Stiles' office, Wymore stares at simulations he's created to uncover the secrets of an elusive enzyme, aldehyde dehydrogenase. ALDH is one of the largest families of enzymes found in most living organisms; in humans, it is involved in breaking down ethanol, for example. Wymore and colleagues at PSC are using simulations to pick apart, atom by atom, how this enzyme operates at its active site. They have discovered an unusual mechanism of action, whereby the enzyme activates a proton transfer from its main chain. Wymore and colleagues demonstrated that without the proton transfer, the enzyme produces a dead-end product, one that is at the end of an energetically inert pathway. MCell simulation of the neuromuscular synapse between a nerve cell (translucent blue) and underlying muscle cell (green). The nerve contains an array of specialized structures, called active zones, from which neurotransmitter molecules are released when the nerve fires. To make this model, a single active zone geometry was created with computer-aided design software based on electron microscope measurements. Cyan spheres are synaptic vesicles. Calcium ions (yellow) enter through the transmembrane ion channels and can also bind to many intrinsic buffer sites (magenta). Courtesty of Joel Stiles / PSC Thanks to X-ray crystallography and sequencing experiments, Wymore knows that the simulations he is running were, at least in structure, an accurate representation of what's happening in vivo, and he feels confident that the model has shed light on a completely new mechanism. New research by Wymore's group, to be published this month in Biochemistry, suggests a link between this mechanism and two metabolic diseases, Sjogren-Larsson syndrome and type II hyperprolinemia. The researchers argue that both diseases are caused by inherited mutations, which prevent ALDH from completing the necessary proton transfer. Wymore is already exploring, using simulations, whether it's possible to insert a molecule into the enzyme active site, which will facilitate the proton transfer, potentially leading to a viable treatment. In order to estimate the action of ALDH at its active site, each of the simulations needs to be computed on a portion of the processors that comprise the supercomputers, some simulations taking several weeks. BigBen's processor time is split among the 2,000 researchers who use it; some projects can demand up to one million processor hours at a time. Wymore's Biochemistry findings required 15,000 hours on 900 of BigBen's processors, and 50,000 hours on another Westinghouse computer, dubbed Jonas. The largest allocation of processor time - six million processor hours - was given to researchers in particle physics. In general, chemistry and molecular and cellular bioscience research comprises about 49% of supercomputer usage. According to Ralph Roskies, codirector of PSC, one of the most significant findings to emerge from the PSC supercomputer came from work by Klaus Schulten at the University Illinois, Urbana-Champagne. The researchers took advantage of TeraGrid (as fast as 35,000 desktop computers) to produce detailed images of the nuclear pore complex, which was then a little-known set of proteins that regulates the traffic of other proteins passing through the nuclear membrane. The complex is large, with a mass of 125 megadaltons in vertebrates. Schulten's research focused on the importin-â transport receptor and how it interacts with the nucleoporins in the complex that are involved in transport selectivity.2 Schulten's group confirmed three of the four binding sites of the FG-Nups protein to importin-â, which were previously identified in electron microscopy experiments. They also identified six novel binding sites, one of which has already been verified by experimentation. In a dimmed computer lab, Stiles is teaching 14 high-school students a basic example of how to program a biological simulation. The students sit at their monitors, facing a long projection screen. Stiles is guiding them on designing a program that will count the number of blue and red ligands in a molecule. The students follow along with Stiles, as he demonstrates the process of programming a simulation using MCell and DReAMM. Both programs work in tandem to visualize cell physiology and processes, such as the mechanism of action of neurotransmission at neuromuscular junctions (References 1. J. Coggan et al., "Evidence for ectopic neurotransmission at a neuronal synapse," Science , 309:446-51, 2005. [PUBMED] 2. T. Isgro, K. Schulten, "Binding dynamics of isolated nucleoporin repeat regions to Importin-â," Structure , 13:1869-79, 2005. [PUBMED]

The Bytes Behind Biology

The Bytes Behind Biology

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