Understanding how proteins fold.

Scientists long to figure out the rules for how protein strands curl into their particular three-dimensional shapes. Understanding these principles could provide insight into biological processes and enable scientists to make proteins for specific uses.

Two recent studies move researchers closer to those goals. One boosts the basic knowledge of how proteins fold; the other offers a practical way of putting such knowledge to use.

Many scientists think that the formation of weak bonds between hydrogen and other elements, especially nitrogen and oxygen, helps proteins lock into their final shapes. To test this idea, Jeffrey S. Moore and Peter G. Wolynes of the University of Illinois at Urbana-Champaign and their colleagues synthesized short chains of phenylacetylene molecules, which don't contain elements that form hydrogen bonds, and dissolved them in a liquid.

The researchers found that the chains folded into spiral structures resembling alpha helices in proteins, suggesting that hydrogen bonds are not central to the folding of alpha helices. The chains wrap around themselves in order to minimize contact with solvent molecules, the researchers argue in the Sept. 19 Science.

In the second study, Bassil I. Dahiyat and Stephen L. Mayo of the California Institute of Technology in Pasadena reversed the usual strategy, which is to predict a protein's three-dimensional structure from its amino acid sequence. Instead, they developed a way to find the best string of amino acids to make a chosen shape.

As a target, the researchers chose a structure called a zinc finger, which helps certain proteins bind to DNA. This small module of 28 amino acids folds into a well-defined shape that contains many of the features found in larger proteins. Using a supercomputer, Dahiyat and Mayo sorted through the many possible combinations that could make up a 28-amino-acid segment. They combined available theoretical models and empirical results to predict each sequence's three-dimensional structure.

After finding the closest match to the target shape, the researchers synthesized that sequence in the lab and determined that its structure was nearly identical to that of the actual protein. "By combining theory, computation, and experiment," the researchers say, "[the method] has improved our understanding of the physical chemistry governing protein design." They report their findings in the Oct. 3 Science.