NET NEWS: Watching an Enzyme Find Its Groove

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Science  21 Aug 1998:
Vol. 281, Issue 5380, pp. 1107
DOI: 10.1126/science.281.5380.1107d

If you think Michael Jordan has quick moves, consider the enzyme that helps his nerves fire—it regularly slam-dunks key signaling molecules in quintillionths of a second. Yet the enzyme, called acetylcholinesterase (AChE), appears ill-suited for its task. Now a play-by-play computer model suggests that AChE's secret is incredibly rapid wiggling.

AChE breaks down the neurotransmitter acetylcholine (ACh) so that signals between neurons will be distinct. That's a seemingly tough task, because ACh must enter a cleft in the enzyme that's blocked by a mobile ring of molecules more than 97% of the time. University of California, San Diego (UCSD), biochemist Andrew McCammon wondered how the enzyme could be so efficient despite the odds against ACh ever binding to it.

To find out, a UCSD, University of Houston, and Drexel University team used supercomputers to model subtle shape changes in AChE that last about a billionth of a second. They simulated the motion of about 130,000 individual atoms in the enzyme and the water molecules that surround it. The results showed that the entrance to the cleft opens and shuts so frequently that any ACh molecules loitering nearby have ample chances to diffuse in. They also found that molecules just a smidgen larger can't easily enter the cleft—a mechanism for keeping the binding site clear. (To see a movie, go to chemcca10.ucsd.edu/java_movie2/GorgeF.html)

The work, described in the 4 August Proceedings of the National Academy of Sciences, is an excellent combination of theory and computer simulations, says Attila Szabo, a theorist at the National Institutes of Health.

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