Volume 3, Issue 6 August 2003

2003
2002
2001

A Less is More Approach to Protein Modeling by David Pescovitz Printer-friendly version Professor Teresa Head-Gordon's cross-disciplinary research combines experimental, theoretical, and computational approaches. Angela Privin photo In Teresa Head-Gordon's laboratory, an IBM supercomputer cranks out dreamlike visualizations that are reminiscent of artist Salvador Dali's surreal landscapes. But these stunning graphics are not eye-candy, they're precise representations of proteins, the building blocks of human life. Ultimately, the bioengineering professor's mind-boggling models could lead to cures for diseases like Parkinson's and Alzheimer's. Head-Gordon's efforts are focused on simplifying protein models so that scientists can more easily understand how proteins form and potentially alter disease-causing characteristics. Proteins consist of long chains of 20 kinds of amino acids linked together under instruction from DNA. Once the chain is complete, the protein literally folds itself up so that only a portion of the resulting molecule is exposed to react with the environment around it. For example, the shape of the protein hemoglobin makes it ideal for the transportation of oxygen through the bloodstream while collagen is perfectly structured to form connective tissue. The detailed protein folding model (top) above is much more complex and difficult to analyze than Head-Gordon's minimalist model (below) of the same molecule. (Click on image to download larger version.) Image courtesy the researcher One unusual property of proteins is that even though their concentration in the body may be incredibly dense, they avoid clumping together, a phenomena known as aggregation. Protein aggregation around nerve cells is associated with the debilitating symptoms of Parkinson's, Alzheimer's, and other diseases. "There's something specific in the sequence of amino acids that essentially can result in aggregation," Head-Gordon says. "So if we can understand those molecular processes at the sequence level then in principle we could potentially re-engineer these disease proteins to avoid aggregation." Head-Gordon's innovation lies in her minimalist protein models. Think of a protein as a necklace beaded with various amino acids. Rather than model each bead— a computationally-difficult and time consuming process —Head-Gordon categorizes the beads into just three flavors based on their physical interactions during folding. While this coarseness of detail does not depict every component of a protein, it represents enough to provide scientists with insight into what combinations of beads may result in aggregation. After Head-Gordon generates a model, her collaborator in the Department of Chemical Engineering, professor Harvey Blanch, verifies in vitro whether the engineered proteins aggregate as predicted by the simulation. "The reduced computational cost at the coarse-grained level of abstraction will potentially enable both folding studies on a genomic scale and systematic application in protein design," Head-Gordon and postdoctoral researcher Scott Brown write in a recent scientific paper. Doe you think that a better understanding of protein folding will help find cures for Parkinson's or Alzheimer's diseases? We want to hear from you... While the minimalist models could someday lead to gene therapies for certain diseases, Head-Gordon says those health-related applications are not in the near-term. More immediate, she explains, are benefits for biotechnology companies that produce proteins for pharmaceutical use and research. Often, the synthesis machinery in the bacteria that the biotech industry uses to produce proteins becomes overwhelmed. This results in the over-expression of the protein and, ultimately, protein aggregation. A denaturing step is then required to reverse the aggregation. Engineering the proteins not to aggregate would reduce the cost of this intermediate step and enable the company to produce more proteins in a shorter period of time. From today's biotech industry to tomorrow's gene therapies, Head-Gordon's minimalist models are proving that less is indeed more. "Sometimes when you have so much detail, you get lost in the forest," Head-Gordon says. "With minimalist models, things are much easier to characterize, analyze, and understand." Teresa Head-Gordon's Research Group The Blanch Lab Lab Notes is published online by the Public Affairs Office of the UC Berkeley College of Engineering. The Lab Notes mission is to illuminate groundbreaking research underway today at the College of Engineering that will dramatically change our lives tomorrow. Editor, Director of Public Affairs: Teresa Moore Writer, Researcher: David Pescovitz Designer: Michele Foley Subscribe or send comments to the Engineering Public Affairs Office: lab-notes@coe.berkeley.edu. © 2003 UC Regents. Updated 7/31/03.