University of California researchers map key cellular structures with a new supercomputer adapted methodSan Diego 22 August 2001 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. 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).
"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 work did
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.
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