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Tracing tRNA's Tricky Tango

27 October 2005 (All day)
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Getting things straight. A computer simulation charted the hypothetical path of a transfer RNA--shown here in yellow with a budding protein (green)--as it lines up in position within the ribosome (gray and purple).

Scientists have employed the sixth fastest computer in the world to simulate in rich new detail how the microscopic cellular factory called the ribosome accurately constructs proteins. Although the technical achievement has shattered the previous record for biological simulation and impressed researchers, ribosome specialists are wary of the study's conclusions.

During the translation of genes to proteins, molecules known as transfer RNAs or tRNAs dock along another RNA molecule, an mRNA, within the ribosome and deliver an amino acid building block to a growing protein. The mRNA codes for each amino acid using a unique codon: a sequence of three adjacent nucleotides in the genetic code. The goal of the simulation was to see how the bacterial ribosome differentiates between similar codons to avoid errors. That could suggest particularly important ribosome elements that might be new targets for antibiotics.

To tackle the problem, Los Alamos computational structural biologist Kevin Sanbonmatsu used the Advanced Simulation and Computing Q machine at Los Alamos National Laboratory in New Mexico. Employing a technique called molecular dynamics, he was able to simulate how millions of interactions allow an amino acid to navigate into place during the protein-building process. The results suggest that the tRNA has an extra hinge where it holds the amino acid. There also appears to be a special loop in the ribosome through which the end of the tRNA must writhe. If the tRNA codon is misaligned with the mRNA--say, if only two of three RNA bits are correctly matched--the tRNA might hit this loop as it passes, the researchers report online this week in the Proceedings of the National Academy of Sciences (PNAS). New drugs that disrupt this gateway in bacterial ribosomes could be effective antibiotics, the researchers believe.

Because of limitations in computing power, Sanbonmatsu had to speed up the simulation to occur tens of millions of times faster than it occurs naturally within the cell. He acknowledges that the resulting simulation is therefore only a suggestion of the true path the tRNA must follow. But co-author Simpson Joseph, a University of California, San Diego, biochemist, points to published experiments that support the still-hypothetical wiggling dance.

The results "are no doubt controversial," says biochemist Olke Uhlenbeck of Northwestern university in Evanston, Illinois, who edited the paper for PNAS. But he says they're valuable because they suggest further experiments, like mutation studies that could validate the simulated choreography. Given the weaknesses of the simulation, Stanford structural biologist Joseph Puglisi says he wishes Sanbonmatsu had focused on a less complex part of the ribosome. "[T]here's just nothing here to sink your teeth into as an experimentalist," he notes.

Related sites
See a movie of the simulation
The paper

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