Molecular machine could develop drugs for bioweapons victims

September 30, 2002

LOS ALAMOS, N.M., Sept. 30, 2002 - Researchers at the Department of Energy's Los Alamos National Laboratory have created the first computer model of a key part of the E-coli ribosome, a cellular structure responsible for the creation of proteins, that has applications in the development of new and powerful antibiotics for use in the treatment of illnesses caused by all pathogens, including a host of bioweapons agents.

The research was published Sept. 16, 2002 in the online version of Nature Structural Biology and will be published in the Oct. 2002 print edition.

A ribosome's function in a biological system is to de-code the instructions in the cell's DNA for making proteins, essential for the growth and survival of the cell. Many antibiotic drugs work by forcing the ribosomes of disease-causing microorganisms to malfunction, killing the microorganism and curing the disease.

The Los Alamos model, the largest atomic-level asymmetrical biomolecular complex ever modeled - identifying the position of approximately 90,000 individual atoms - was developed by Chang-Shung Tung and Kevin Sanbonmatsu of the Lab's Theoretical Biology and Biophysics group and Simpson Joseph of the University of California, San Diego.

"This structural model is very useful to drug designers developing new antibiotics and a large research community doing studies of the E-coli ribosome in test tubes and in living systems," said Tung. "Our technique can be used for studying the functions of antibiotics on ribosomes from bacteria that can be used as potential biowarfare agents, such as anthrax, brucellosis, cholera, plague, shigella, tularemia, Q-Fever and typhus."

This new model is proof that large protein ribonucleic acid (RNA) complexes can be predicted on a computer, which opens up the possibility for rapidly modeling ribosomes from a variety of organisms. "The developed technique is very useful in structural and functional genomics - understanding how the basic building blocks of life work - and can be used side by side with other experimental methods like X-ray crystallography, Nuclear Magnetic Resonance and electron microscopy," said Sanbonmatsu. "This is a significant step in the Department of Energy's project to 'bring the genome to life' and other functional genomic efforts."

Completing the E-coli ribosomal model was a significant computational challenge given the large number of atoms present in the ribosomal structure and the development of both hardware and software applications used for executing the calculation, said Tung. "Los Alamos National Laboratory is uniquely suited for large-scale highly-complex non-linear computational problems and is now at the forefront of modeling for the study of ribosomal-antibiotic interactions," said Tung.

In the future Tung and Sanbonmatsu plan to create similar all-atom structures for the ribosomes of other disease-causing microorganisms, also with the goal of giving antibiotic researchers valuable tools in the fight against disease, particularly diseases caused by bioweapons.
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Los Alamos National Laboratory is operated by the University of California for the National Nuclear Security Administration (NNSA) of the U.S. Department of Energy and works in partnership with NNSA's Sandia and Lawrence Livermore national laboratories to support NNSA in its mission.

Los Alamos enhances global security by ensuring the safety and reliability of the U.S. nuclear stockpile, developing technologies to reduce threats from weapons of mass destruction, and solving problems related to energy, environment, infrastructure, health and national security concerns.

For more Los Alamos news, visit www.lanl.gov.

(Editors: Image Available Online: http://www.lanl.gov/orgs/pa/News/Ribosome.html)

DOE/Los Alamos National Laboratory

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