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Proteins by design

Basic Sciences Division, UW collaborators demonstrate mastery over mystery with creation of original protein
A representation of Top7, a novel protein successfully designed and built using a computer program. image courtesy of Stoddard Lab

For the first time, scientists have successfully used a computer program to design and build a novel protein never before seen in nature.

The engineering feat, a collaborative effort of the labs of Dr. David Baker at the University of Washington and Dr. Barry Stoddard in the Basic Sciences Division, represents a major leap in scientists' understanding of how the three-dimensional molecules that carry out all of life's activities fold into their proper shapes. The ability to create designer proteins with specific functions could pave the way for creating novel therapeutic molecules for treating cancer and other diseases.

"This is a huge jump forward in protein design," Stoddard said. "Previous attempts involved redesigning natural proteins to contain novel features. But for this study, David said, 'let's choose something never before observed.'"

In achieving that goal, the research team demonstrated man's mastery of the mysterious set of rules nature uses to design life's workhorse molecules.

Stoddard said the fact that they could design an artificial protein suggests that there may be many as yet undiscovered protein possibilities. "Since all living things are derived from a common ancestor, nature has probably only sampled a small subset of all of the possible protein folds that could be formed," he said.

Dr. Brian Kuhlman, a former postdoc in Baker's lab, led the study, which appeared in the Nov. 21 issue of Science. Collaborators included Gautam Dantas, a graduate student in Baker's lab; Gregory Ireton, a former graduate student in the Stoddard lab; and Dr. Gabriele Varani, UW professor of chemistry.

Proteins are three-dimensional molecules that adopt their structures based on a linear sequence of the 20 protein building blocks, or amino acids. When strung together in different combinations with different numbers of building blocks, proteins can fold into an almost infinite number of shapes.

A protein's unique shape determines its function. For example, hemoglobin contains a pocket for ferrying oxygen through the blood, while myosin's string-like shape enables it to form muscle fibers. For nearly 50 years, scientists have attempted to learn the rules that govern how proteins coil, twist and bend into their characteristic shapes based on their linear sequence of amino acids.

Several years ago, Baker's lab developed a computer program called Rosetta that has proven successful in predicting the three-dimensional shape of natural proteins based on their amino-acid sequence. X-ray crystallography, a technique used in Stoddard's lab to determine molecular structures, confirms the predictions.

For this study, Baker's lab asked the program to design a novel protein that consisted of 93 building blocks, or amino acids, and to predict its three-dimensional structure based on the amino-acid sequence. The researchers then synthesized a gene capable of making that protein, which they inserted into the bacterium E.coli. Once bacteria produced enough of the protein, named Top7, Stoddard's lab determined its structure using X-ray crystallography and found it to be identical to that predicted by the computer program.

Stoddard said that the next obvious application of this technology is to create what he called "protein folds with function." Top7 performs no known useful activity.

"One important application would be to create a protein that serves as an inhibitor for a step in an undesirable metabolic pathway for which there is no known small molecule inhibitor," he said. "That sort of metabolic engineering is the basis for drug design."

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