A new way to synthesize 'natural' proteins.

Nature seems to do it so effortlessly -- forge proteins, that is.

These complicated bundles of amino acids, elegantly aligned to fold into three-dimensional sculptures of exact proportions, perform essential biological tasks. Yet synthesizing proteins has proved extremely difficult.

Chemists have likened the process to building a minuscule house in the dark with molecule-size bricks.

Now, Stephen B.H. Kent, a biochemist at the Scripps Research Institute in La Jolla, Calif., and his colleagues report a new technique for fashioning proteins in the laboratory. Their report of "native chemical ligation" appears in the Nov. 4 SCIENCE.

"Making large peptides or proteins is very hard to do if you try to build them one amino acid at a time," says Philip E. Dawson, a chemist at Scripps and a coauthor. "We're good at making peptides with 50 to 70 amino acids. But if you want to make a protein with 100 to 200, even 300, amino acids, you need to be able to join larger units together."

Recent attempts at building bigger proteins have involved several types of chemical ligation, whereby chemists link up peptides, or protein fragments, in series, says Dawson.

Trouble can arise in the links, though. Synthetic methods typically use "unnatural" bonds, rather than the types normally found in proteins, to glue chains of amino acids together.

With this new method of protein synthesis, the bonds holding together the protein's key components resemble nature's own -- hence the phrase "native chemical ligation."

To exemplify the new procedure, Kent and his crew cobbled together two large peptides -- one with 33 amino acids and the other with 39 -- to create an exact replica of human interleukin-8, an immune system protein with 72 amino acids.

This technique should work for any series of amino acids or any protein, says Dawson. "So the next step is to generalize this work and apply it to many kinds of biological problems to learn more about how enzymes work.

"In this paper, we showed how to connect two peptides," Dawson adds. "But in theory, this technique can join four or five peptides in series, which would allow someone to make larger proteins."

In time, this ligation technique will help scientists probe enzyme function. "To really understand how a protein or enzyme works, you have to make small changes in its structure and observe the consequences," Dawson says. "The finer the changes, the more carefully you can tune your experiments."

Tom W. Muir, a biochemist at Scripps, points out that this new way of joining peptides will augment another, DNA-based tool for making proteins. "There are things that this method can do that DNA recombination technology can't do and vice versa. So the two techniques complement, rather than compete with, each other."

"Many proteins in nature are made of well-defined [pieces]," says Muir. By using this method to link together those pieces, researchers will be able to synthesize types of proteins "that weren't possible before."