ACADEMIA

Researchers using a Cray XT3 supercomputer at Pittsburgh Supercomputing Center (PSC) have succeeded in uncovering vital information about how bacteria develop resistance to antibiotics. Nicknamed BigBen, PSC's Cray XT3 system is being employed by biophysicists to create complex simulations that help explain how certain enzymes produced by bacteria prevent antibiotic medicines such as penicillin and its derivatives from curing infections. The National Health Council estimates that as many as 14,000 hospitalized Americans die annually because available antibiotics no longer work effectively. Since they reproduce and mutate quickly, bacteria are constantly evolving countermeasures to existing treatments. Molecular biologists use high performance computers such as the Cray XT3 supercomputer to help them win the "arms race" against harmful bacteria's chemical defenses. "The clinical use of beta-lactams, the type of antibiotics most commonly prescribed today, has exerted evolutionary pressure on bacteria, triggering several resistance mechanisms," says University of Pennsylvania biophysicist Matteo Dal Peraro. "One of the most effective of the bacteria's defenses is the synthesis of beta-lactamases, a group of enzymes that inactivate antibiotic drugs. The most dangerous of the newly evolved beta-lactamase enzymes are known as metallo beta-lactamases because they include zinc metals in their structure. The bacteria that contain these enzymes don't respond to multidrug regimens such as augmentin and pose a serious health threat if massively spread." Dal Peraro collaborates with Prof. Michael Klein, who directs the University of Pennsylvania's Center for Molecular Modeling and leads a range of studies on enzymes and how they catalyze biological reactions. "For the kinds of calculations our group does, the Cray XT3 supercomputer is the most productive resource available to us," says Klein. "It allows us to undertake projects we couldn't accomplish before in a reasonable timeframe." The role of zinc in the metallo beta-lactamases enzyme reaction has not been well defined, despite extensive study. Klein and Dal Peraro designed a simulation that tracked a particular enzyme by applying an approach called first principles quantum mechanics/molecular mechanics (QM/MM) dynamics to the problem. When BigBen first became available in late 2005, the scientists were able to leverage the immense processing power of the system to conduct parallel simulations that scanned the reaction pathway in several windows over a total simulated reaction time of ~100 picoseconds (~100 trillionths of a second). One of their findings revealed that the dizinc form of the enzyme (with two zinc atoms at the active site) is the most efficient and ultimately the most dangerous in terms of its antibiotic inhibiting power. Another surprising finding has to do with how the zinc ions shift the way they bond to other molecular groups (amino acids and waters) for promoting the catalytic reaction. "This shift of metal coordination is of paramount importance in appreciating how the enzyme works," says Dal Peraro. "Experimentally it is really difficult to follow these movements because they're really fast and also because zinc and other transition-metals are not visible to most of the spectroscopic techniques. But with the computational power provided by the Cray XT3 system, we can 'see' what happens during that tiny fraction of a second by modeling the reactive process on the supercomputer." PSC recently doubled the capacity of its Cray XT3 system to over 21 teraflops (trillion floating point operations per second). PSC's system was the first Cray XT3 supercomputer to be installed and became the leading performer among tightly coupled supercomputer architectures on the National Science Foundation's TeraGrid computing infrastructure. A research paper, "Role of Zinc Content on the Catalytic Efficiency of B1 Metallo beta-Lactamases" by Dal Peraro, Klein, Paolo Carloni and Alejandro Vila, has been published in the Journal of the American Chemical Society 129(10), 2802-2816 (2007). More information is also available at its website.