NEWS OF THE WEEK COMPUTATIONAL
CHEMISTRY
CREATING CUSTOM PROTEINS Novel proteins designed in silico, created successfully in vitro MADE TO ORDER Hellinga's computational methods produce huge libraries of mutant proteins, including one that binds well to TNT (top).
ENERGY
U
SING A COMPUTER, DUKE
University chemists have redesigned proteins to perform entirely new, unnatural functions. Then, the scientists have created these customized proteins in the lab and showed that they do their assigned jobs well. The feat represents a big step forward for both directed evolution—in which protein functions are altered by creating and selecting numerous mutations— and for computational chemistry's ability to accurately describe the complex interactions and functions of proteins.
The computer removes the limitations of time and search space in a lab, allowing chemists to rapidly examine enormous numbers of possible mutants. The potential applications of these new design techniques range from sensors to chiral separations to enzymes. Associate biochemistry professor Homme W. Hellinga and colleagues at Duke chose as their starting point the superfamily of medium-sized periplasmic binding proteins in E. colt. The proteins have hinged structures that clamp down onto a ligand—a sugar or amino acid. The receptors in new versions of the proteins are engineered to bind to a series ofentirely different ligands, including the explosive trinitrotoluene (TNT), the neurotrans-
BILL
Senate Debates Ethanolp MTBE Amendments
T
he Senate opened its debate last week on the Energy Policy Act (S. H ) , a complicated measure that will attract hundreds of amendments and take weeks to finish. The energy package will be merged with a $15.7 billion energy tax incentive bill (S. 597). One of the first amendments will mandate increased use of ethanol in gasoline. Bipartisan support is expected for this measure, which would double ethanol use by 2012, among other provisions. Another expected amendment bans the use of methylterf-butylether (MTBE) as a gasoline additive because it causes groundwater pollution problems. And Senate Democrats have promised to offer amendments promoting use of alternative fuels. Amendments to curb releases of C02 and other air emissions and to permit oil drilling in the Arctic National Wildlife Refuge are ex-
pected to be the most contentious. The ANWR provision, especially, has split Republicans and Democrats. The Republican-controlled House passed its version of an energy bill (H.R. 6) in April, which does include approval for ANWR drilling.
Frist
"ANWR is part of a national energy policy, so I'd be surprised if there was not at least a discussion on the floor," said Senate Majority Leader Bill Frist (R-Tenn.). Major differences, such as ANWR drilling, between the House and Senate legislation resulted in no energy bill being passed last year.—DAVID HANSON
mitter serotonin, and L-lactate [Nature, 423,185 (2003)]. Hellinga's work, says computational chemist William A. Goddard III at California Institute of Technology, represents a "breakthrough in computational design of receptors." Stephen L. Mayo, associate professor of biology and chemistry at Caltech and a pioneer in computational protein design, says the work illustrates the field's evolution. "This clearly shows now that you can make the transition from doing just structure design to doing function design." The periplasmic binding protein superfamily, with its many natural variants, was a promising place to start. "Nature is saying this is a really nice motif to evolve," Hellinga says. Hellinga's group, including grad students Loren L. Looger and Mary A. Dwyer and postdoc James J. Smith, created new and augmented well-known computational strategies, docking different ligands and simultaneously evolving the protein tofitthem. The result was vast libraries of 1053 to 1076 possible choices. They whittled their selection down to just 17 compounds with promising binding characteristics. Amazingly the calculations required only modest resources—a computer cluster of 30 processors. Then, in the lab, the team created those 17 proteins, which performed as they'd hoped. Drawing on previous work, the group inserted a tag on the protein that fluoresces when it binds, as a marker of the mutants' abilities. Additionally the mutants retained the natural proteins' ability to drive signal transduction pathways. Ultimately, chemists seek the ability to design enzymatic catalysts, notes William F. DeGrado, professor of biochemistry and biophysics at the University of Pennsylvania School ofMedicine, who wrote a commentary accompanying the article. Hellinga's group hopes to do just that.— ELIZABETH WILSON
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C & E N / MAY 12. 2003
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