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NEWS OF THE WEEK
SCIENCE
August 27, 2001
Volume 79, Number 35
CENEAR 79 35 p. 13
ISSN 0009-2347
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MODELING BIOSTRUCTURES
'Parallel focusing' yields electrostatic maps of huge bioassemblies

STU BORMAN, C&EN WASHINGTON

A collaborative research group has developed a computational technique that makes it possible to model electrical charge distributions in biomolecular structures more than an order of magnitude larger than those previously accessible. Up to now, electrostatic modeling has been limited to structures of about 50,000 atoms or fewer, but the new method can be used to map charge distributions in macromolecules, supramolecular complexes, and cell organelles containing more than a million atoms.

7935fig3-redux
7935fig3-redux
CHARGED UP These electrostatic maps of a microtubule (top) and its two opposite ends (middle and bottom) were obtained with the parallel focusing technique. Blue represents positive charge; red represents negative charge.
The technique, "parallel focusing," was developed by postdoc Nathan A. Baker, assistant professor of biochemistry Simpson Joseph, associate professor of mathematics Michael J. Holst, and chemistry professor and Howard Hughes Medical Institute Investigator J. Andrew McCammon of the University of California, San Diego, and assistant professor of biomedical engineering David S. Sept of Washington University, St. Louis [Proc. Natl. Acad. Sci. USA,
98, 10037 (2001)].

Electrostatic interactions play an essential role in many cell processes, such as the transmission of nerve impulses in neurons, and charge-density maps provide invaluable information about the stability, motions, binding interactions, and mechanisms of biomolecular structures.

The parallel focusing technique makes it possible for the power of multiple computer processors to be combined to solve the Poisson-Boltzmann equation, one of the most widely used relationships for calculating molecular electrostatic potentials. "The beauty of the method lies, in part, in its simplicity," notes professor of biochemistry and structural biology Benoit Roux of Weill Medical College of Cornell University, New York City. Baker and coworkers "have succeeded in formulating a huge intractable problem into a large number of small tractable calculations," he says.

Baker and coworkers demonstrated the capabilities of the technique by obtaining electrostatic maps of ribosome subunits containing 88,000 and 95,000 atoms and cell microtubules 1.2 million atoms in size. The microtubule map revealed larger than expected electrostatic variations across the structure, potentially significant charge features at sites where drugs bind, and dramatic differences in charge properties at the two ends of the structure.

The work could lead to a better understanding of the stability and dissociation mechanism of microtubules. It may also have therapeutic applications, because it could help explain why some drugs destabilize microtubules and others, such as the anticancer agent Taxol, have the opposite effect.

The parallel focusing technique is based on an algorithm developed earlier by UCSD mathematics professor Randolph E. Bank and Holst. The algorithm divides problems into small parts that can be solved by parallel processing--the simultaneous use of multiple processors. But the algorithm wasn't applicable to the type of calculation typically used to solve the Poisson-Boltzmann equation. The parallel focusing technique adapts the algorithm for that type of calculation and thus dramatically reduces the time required to obtain electrostatics solutions.

For example, Baker and coworkers obtained their microtubule model in less than an hour by running a parallel focusing routine on a multiprocessor supercomputer at the San Diego Supercomputer Center (SDSC). They estimate that this same calculation would have required at least 350 times more processor power or computing time if conventional electrostatic methods had been used.

The approach "enables investigators to do all the things they could do with electrostatic models before--for example, exploring binding energies and associations of proteins--but on a far larger scale that is much more relevant to cellular processes," McCammon says. He and his coworkers believe time-dependent electrostatic data will also be accessible, and they note that parallel focusing problems can be solved not just on supercomputers but on networks of small workstation computers as well.

Baker says the group plans to make software for the parallel focusing technique freely available to the scientific community. The group is also working with people at SDSC's National Biomedical Computation Resource "to turn this into a Web-based application, which should further increase the accessibility of the software," Baker says.

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