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February 24, 2005

Understanding protein structure

Understanding the principles that govern the interactions within and between macromolecules is at the foundations of modern molecular biology. This is what Dr. David Baker, associate professor of biochemistry, and his lab have been researching for the past five years.

“The way that we test our understanding is by trying to predict the structures of naturally occurring proteins, protein-protein and protein-DNA complexes, and by trying to design new structures and complexes not found in nature,” Baker said.

The prediction and design calculations are carried out using a computer program called Rosetta. To predict a structure given an amino acid sequence, the program searches for the lowest-energy 3-D structure for that sequence. The laws of physics say that at equilibrium all systems will adopt their lowest-energy states.

To design a sequence that will fold up to a desired structure, the program searches through all the different shape combinations of the 20 amino acids for the lowest energy sequence for the desired structure. Both the physical model and the search algorithms are continually being improved based on feedback from the prediction and design tests.

A grand challenge of computational protein design has been the creation of novel proteins with arbitrarily chosen 3-D structures. This challenge has been realized with the development of a new protein called Top7 with a novel sequence and topology. The X-ray crystal structure of Top7 is strikingly similar to the design model. Top7 was designed and synthesized using protein design-sequence algorithms and the Rosetta structure-prediction program. It is the first globular protein with a new fold that was designed from scratch and validated by its X-ray crystal structure.

Baker notes that designing arbitrary protein structures can help researchers better understand naturally occurring proteins and how they evolved, as well as provide potential tools for drug treatments that would not be possible with proteins found in nature. Custom-designed proteins could also possibly be used as catalysts in reactions and act as new motors for moving things in new ways at the cellular level.

In addition to designing proteins, Baker is also researching how to predict a protein’s structure. At international blind tests of structure prediction methods carried out over the past six years, Baker and colleagues have been consistently ranked the best in the world at interpreting amino acid sequences and predicting their 3-D structures.

Almost all biological processes involve interactions and communications between sets of proteins, and Baker’s group has made progress in both predicting and designing these interactions. “We’ve gotten quite good at taking two structures and predicting exactly how they fit together,” Baker said.

The work involves redesigning the interface at which the two proteins interact to understand interaction specificities, or the number of other proteins a particular protein will interact with. A protein has a high interaction specificity if it will pair up with very few proteins. aA low specificity means a protein will interact with many other different proteins.

Many proteins interact at high specificities. Baker and members of his lab have been able to take a pair of proteins that interact with one another and create new pairs in which each of those new partners interact with one another, but not with the original one, to create a new protein-protein interaction specificity.

“We have a computer model of the protein-protein complex. Then we vary the amino acid sequence at the protein-protein interface, looking for low-energy combinations of amino acids,” Baker said.

Baker will speak on “Prediction and Design of Macromolecular Structures, Interactions, and Functions” at noon on Thursday, March 3, in Hogness Auditorium in the Health Sciences Building as part of the 2004-05 Science in Medicine series. The lecture is open to all faculty, staff and students. Registration is not required.

Baker received his B.A. degree at Harvard University, his Ph.D. at the University of California, Berkeley, and carried out his postdoctoral work at UC San Francisco before joining the faculty at the UW in 1994. He is also an adjunct professor in genome sciences, bioengineering, and physics, and an assistant investigator for the Howard Hughes Medical Institute.

Baker has received young investigator awards from the National Science Foundation, Packard Foundation, Beckman Foundation, Protein Society and the International Society for Computational Biology. His Science in Medicine lecture was rescheduled from the original date in October so that he could be in Washington, D.C. to receive the Feynman Prize in Nanotechnology from the Foresight Institute.