Electrostatics describe the way in which the landscape of electrical charge is laid out in a molecular environment, for example, the electric forces that drive the binding of drugs or proteins to microtubules or that place an RNA molecule on a ribosome during translation of genetic information.

The researchers have mapped both a microtubule and a ribosome, structures that make proteins, using a new computational method that works exceptionally well with very large biomolecular systems.

These maps could enlighten researchers about the structure and function of these large macromolecules, including how a drug such as taxol, used to treat breast cancer, binds to microtubules.

David S. Sept, Ph.D., assistant professor of biomedical engineering at Washington University in St. Louis, created a model of a microtubule on the order of 1.2 million atoms.

Using this structure, he and his UCSD colleagues applied a new algorithm that allowed them to solve the Poisson-Boltzmann equation. By using this new algorithm, they were able to increase the size of the systems they could model from less than 50,000 atoms to over an unprecedented million atoms.

The work was overseen by J. Andrew McCammon, Joseph E. Mayer Professor of Theoretical Chemistry at UCSD and a Howard Hughes Medical Institute investigator.

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.

"We've achieved a new landmark in the scale of cellular structures that we can model from a molecular perspective," McCammon said. "The work signals a new era of calculations on cellular-scale structures in biology."

"The calculations were done in a highly scalable fashion and would be suited to even larger runs," said UCSD's Nathan Baker, Ph.D.,a postdoctoral researcher in McCammon's lab, and first author of the paper who did a majority of the computer implementation. "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."

The rest of the research group was comprised of Michael Holst, Ph.D., UCSD associate professor of mathematics, and Simpson Joseph, Ph.D, UCSD assistant professor of biochemistry.

The calculations were performed at the San Diego Supercomputer Center (SDSC) at UCSD on Blue Horizon, a large IBM supercomputer supported by the National Partnership for Advanced Computational Infrastructure (NPACI). The work was published in the Proceedings of the National Academy of Sciences on August 28, 2001.

Sept and his colleagues used a new algorithm (Bank-Holst) that solved the Poisson-Boltzmann equation enabling them to calculate the electrostatic potentials.

The new computational method assigns a small portion of the calculation to each available processor on the computer. Those processors then 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 maps depict an atom-by-atom rendering of the electrostatic potential of microtubules and ribosomes.

As a result of their calculations on the microtubule, the researchers discovered some areas 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 such as taxol and colchicine may bind. Likewise, the electrostatic map of the ribosome revealed a subunit area that may play roles in stabilizing RNA molecules during translation of genetic information.

Sept and his colleagues created the microtubule from the known structure of the tubulin dimer, which is the protein that forms the building blocks of microtubules.

"It's like we knew what the structure of a brick was, but not the structure of a house," said Sept, who did his postdoctoral work with McCammon. Sept joined the Washington University faculty in early 2001.

"Now, we have a better understanding of the house. We now are better able to calculate on much larger structures, beyond simple proteins and molecules, eventually to the cellular level." - By Tony Fitzpatrick

[Contact: Tony Fitzpatrick ]

17-Sep-2001