Researchers at Los Alamos National Laboratory have set a new world's record by performing the first million-atom computer simulation in biology. Using the "Q Machine" supercomputer, Los Alamos computer scientists have created a molecular simulation of the cell's protein-making structure, the ribosome. The project, simulating 2.64 million atoms in motion, is more than six times larger than any biological simulations performed to date. Today, the effort is featured in a paper in the Proceedings of the National Academy of Sciences.

The ribosome is a living factory, the essential element within cells that creates proteins by decoding each protein type's specific recipe that is stored within messenger RNA. Ribosomes are a fundamental model for future nano-machines, producing the protein building blocks of all living tissue. Credit: Los Alamos National Laboratory

The ribosome is the ancient molecular factory responsible for synthesizing proteins in all organisms. Using the new tool, the Los Alamos team led by Kevin Sanbonmatsu is the first to observe the entire ribosome in motion at atomic detail. This first simulation of the ribosome offers a new method for identifying potential antibiotic targets for such diseases as anthrax. Until now, only static, snapshot structures of the ribosome have been available.

Sanbonmatsu posits that this technique offers a powerful new tool for understanding molecular machines and improving the efficacy of antibiotics. Antibiotic drugs are less than one one-thousandth the size of the ribosome and act like a monkey-wrench in the machinery of the cell. Such drugs diffuse into the most critical sites of this molecular machine and grind the inner working of the ribosome to a halt.

"Designing drugs based on only static structures of the ribosome might be akin to intercepting a missile knowing only the launch location and the target location with no radar information. Our simulations enable us to map out the path of the missile's trajectory," Sanbonmatsu said. "The methods and implications lie at the interface between biochemistry, computer science, molecular biology, physics, structural biology and materials science," said Sanbonmatsu. "I believe the results serve as a proof-of-principle for materials scientists, chemists and physicists performing similar simulations of artificial molecular machines in the emerging field of nano-scale information processing. Sanbonmatu's study focuses on decoding, the essential phase during protein synthesis within the cell wherein information transfers from RNA to protein, completing the information flow specified by Francis Crick in 1958 and known as the Central Dogma of Molecular Biology. "The ribosome is, in fact, a nano-scale computer and is very much analogous to the 'CPU' of the cell," he said.

The ribosome is so fundamental to life that many portions of this molecular machine are identical in every organism ever genetically sequenced. In developing the project, the team identified a corridor inside the ribosome that the transfer RNA must pass through for the decoding to occur, and it appears to be constructed almost entirely of universal bases, implying that it is evolutionarily ancient. The corridor represents a new region of the ribosome containing a variety of potential new antibiotic targets. The simulations also reveal that the essential translating molecule, transfer RNA, must be flexible in two places for decoding to occur, furthering the growing belief that transfer RNA is a major player in the machine-like movement of the ribosome. The simulation also sets the stage for future biochemical research into decoding by identifying 20 universally conserved ribosomal bases important for accommodation, as well as a new structural gate, which may act as a control mechanism during transfer RNA selection.

The aminoacyl-transfer-RNA (red) caught in the act of delivering its amino acid to the growing protein hanging off the peptidyl-transfer-RNA (yellow). The ribosome (large subunit in white and small subunit in cyan) uses the transfer RNA molecules to read the genetic information from the messenger RNA (green). Water molecules are shown in blue. For visualization purposes, only 1 of every 10 water molecules are shown and the top portion of the ribosome is cut away so that the transfer RNA molecules are visible. Credit: Los Alamos National Laboratory

The multi-million-atom simulation was run on 768 of the "Q" machine's 8,192 available processors. Sanbonmatsu worked to develop the simulation with Chang-Shung Tung of Los Alamos, as well as Simpson Joseph of the University of California at San Diego. Funding for the research was provided by the National Institutes of Health, Los Alamos National Laboratory's research and development fund, and support from the Laboratory's Institutional Computing Project.