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SAN DIEGO, CA - August 22 - Researchers at the University of California, San Diego have mapped key cellular structures using a new method to harness the power of supercomputing. The maps may point the way to understanding how those structures perform functions such as transporting a drug like taxol to a binding site so it can do its work in treating breast cancer.

"We've achieved a new landmark in the scale of cellular structures that we can model from a molecular perspective," said J. Andrew McCammon, Joseph E. Mayer Professor of Theoretical Chemistry at UCSD and an Howard Hughes Medical Institute investigator. "The work signals a new era of calculations on cellular-scale structures in biology."

The researchers created a new method for solving what is known as known as the Poisson-Boltzmann equation. This allowed them to increase the size of the systems they could model from less than 50,000 atoms to over an unprecedented million atoms. McCammon likened the ability to pick out one atom within such a large three-dimensional system as being able to specifically describe one cherry within an entire fruit tree.

The maps depict an atom-by-atom rendering of the electrostatic potential of structures found within cells: microtubules, which are involved in intracellular transport and shape, and ribosomes, which manufacture proteins. Electrostatics describe the way in which the landscape of electrical charge is laid out in a molecular environment, for example, the electric forces that draw a taxol molecule through a microtubule and into a binding site or that tug a tRNA molecule into place on a ribosome during translation.

The calculations were performed at the San Diego Supercomputer Center (SDSC) at UCSD on Blue Horizon, a large IBM SP supported by the National Partnership for Advanced Computational Infrastructure (NPACI). The work will appear online in the Proceedings of the National Academy of Sciences on August 21, 2001 and in print on Aug. 28, 2001.

To model the structures, McCammon and a group including Nathan Baker, a postdoctoral researcher in McCammon's lab, Simpson Joseph, assistant professor of biochemistry at UCSD, Michael Holst associate professor of math of UCSD, and David Sept, assistant professor of biomedical engineering at Washington University, created algorithms and wrote computer codes to solve equations that describe the electrostatic contributions of individual atoms within a system. Previous work had been limited by the numbers of atoms that could be modeled at once and how the computers could utilize the code.

The system could be enlarged even further, said Baker. "The calculations were done in a highly scalable fashion and would be suited to even larger runs. We hope to push the envelope even further and to tackle a number of large-scale problems in intracellular activity such as antibiotic binding to ribosomes," he said.

The new algorithm assigns a small portion of the calculation to each available processor on the computer. Those processors then independently solve their portion of the equation and pass the results along to a "master processor" that gathers and processes the data. Blue Horizon completed the calculations for the equation relating to the microtubule in less than an hour using 686 processors available out of 1,152. The researchers estimated that the old method would have required at least 350 times more memory and time to solve.

As a result of their calculations on the microtubule, the researchers discovered some small islands of positive potential in the overall negatively-charged microtubule. They said that while the negative charge likely plays a strong role in intracellular transport, the overall topography points to regions where drugs like taxol and colchicine may bind. Likewise, the electrostatic map of the ribosome revealed an area on the smaller 30s subunit that may play roles in stabilizing tRNA and mRNA during translation.

Baker was supported by a predoctoral fellowship from the Howard Hughes Medical Institute and the Burroughs-Wellcome La Jolla Interfaces in Science program. The research is also supported by IBM/ACS, the NIH, NSF, NPACI/SDSC, and the W.M.Keck Foundation.

SDSC is a research unit of the University of California, San Diego, and the leading-edge site of the National Partnership for Advanced Computational Infrastructure. SDSC is sponsored by the National Science Foundation through NPACI and by other federal agencies, the State and the University of California, and private organizations. For additional information about SDSC, see http://www.sdsc.edu/ or contact David Hart at dhart@sdsc.edu or 858-534-8314.###

Images and Media Contact:
Cassie Ferguson, cferguson@sdsc.edu, (858) 822-3622

Comment:
J. Andrew McCammon, jmccammon@ucsd.edu, (858) 534-2905
Nathan Baker, nbaker@chemcca33.ucsd.edu, (858) 822-0169