Biochemist finds new keys to determining protein structure

David Baker

Computer-generated, multi-colored structures of large proteins are elegant images to behold. Each graceful fold and twist is a molecular key that establishes interactions the protein will have with other molecules, and thus, its function.

When lipoproteins develop, for instance, they fold into a shape that allows them to bind with fats (lipids) and distribute them for fuel throughout our bodies. By figuring out how proteins take shape, researchers hope to unveil their functions.

“Protein folding is one of the great unsolved problems of modern molecular biology,” says expert Dr. David Baker, an assistant professor of biochemistry. “Proteins are huge molecules with thousands of atoms with at least as many molecular interactions.”

How important is this work? As important as understanding the basic units of life.

The development of a protein begins when DNA is transcribed into amino acid sequences. These sequences consist of 20 types of amino acids strung together in a chain-like structure. Sometimes in seconds, sometimes longer, depending on the size of the molecule, this chain “folds up” into the functional 3-D protein.

Baker and colleagues, notably graduate student Kim Simons, recently returned from a meeting at Asilomar in Pacific Grove, Calif., called CASP3, in which they were ranked among the highest groups in the world at interpreting amino acid sequences and predicting their 3-D structures.

CASP3 (Third Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction) received support from the Department of Energy and National Institutes of Health. Earlier this year, a CASP3 organizing group released amino acid sequences for a number of proteins whose structures were in the process of being determined using X-ray crystallography. The group challenged experts from around the world to predict their 3-D structures from the amino acid sequence information alone.

Without knowing how the proteins fold, predicting their 3-D structures accurately depends on understanding the interactions between as many of the amino acid segments as possible. Thousands of interactions make it a massive computational, as well as biophysical, problem.

The key to the success of Baker and researchers in his lab has been figuring out how to simplify the problem while retaining the key features of the sequence.

In a separate set of experiments, Baker and his team developed new techniques that allow them to create amino acid sequences that consist of a subset of five amino acids per segment, and then analyze them as they fold. What they noticed is that the simplified proteins fold similarly to naturally occurring proteins of 20 amino acids that contain the simplified subset.

“You can tell what parts are going to fold first, and you don’t need to know all the interactions between the molecules. The typology of the protein is a major determinant of how it folds,” Baker said.

Baker and coworkers found that there is a strong correlation between how fast proteins fold and how close the amino acid sequences are. “The exciting thing is that protein folding is turning out to be much simpler than we ever expected,” Baker said.

Understanding protein folding will likely first find clinical application in developing therapies for diseases such as Alzheimer’s and cystic fibrosis, which are known to be caused by “misfolding,” Baker added.

Baker received a B.S. in biochemistry from Harvard University in 1984 and a Ph.D. in 1989 from the University of California, Berkeley. He conducted postdoctoral work between 1990 and 1993 in the Department of Biochemistry and Biophysics at University of California, San Francisco, and joined the UW in 1993 as an assistant professor of biochemistry.

His awards include a Packard Fellowship in Science and Engineering and a NSF Young Investigator Award, both in 1994, and a Beckman Young Investigator Award in 1995.

Baker will discuss his research in a Science in Medicine lecture, titled “How Proteins Fold,” on Friday, Jan. 8, from noon to 1 p.m. in room T-625 of the Health Sciences Center. ¶

Will Morton