For the last decade, scientists have been trying to accurately synthesize substances with shapes that mimic biological molecules, specifically proteins that drive important biochemical pathways in humans. So far, these attempts have made moderate strides, both in terms of size of the designed protein and the precision with which it folds from a string of amino acids to its final three-dimensional structure. Now, researchers at the University of Pennsylvania Medical Center have created the largest protein from scratch, with both a stable and predictable shape.
"The ability to do this really takes us out of the realm of tinkering with existing proteins to engineering entirely new proteins and polymers," says senior author William F. DeGrado, Ph.D., professor of biochemistry and biophysics. "We have shown that it is now possible to design a protein with a well-defined three-dimensional structure." The Penn group's findings appear in the May 11 issue of the Proceedings of the National Academy of Sciences.
DeGrado notes that implications of this advance in protein design could be as broad as those for natural proteins -- from manufacturing entirely new polymers for industrial catalysts to creating new pharmaceuticals.
To design a protein, scientists generally work backwards from nature in a two-step process. They first choose an existing three-dimensional protein structure and then, using complex computer programs, find a new sequence of amino acids that folds into the same shape as the natural protein. The Penn team's approach is one step removed from that. "We asked: Can we generate proteins that are inspired by nature but have no direct natural equivalent?," explains DeGrado.
The protein -- called alpha-3D -- was designed, produced, and characterized by Scott Walsh, a doctoral student in DeGrado's lab. Alpha-3D is a bundle of three counterclockwise-coiling helices whose general shape was inspired by a protein found in the common household bacteria Staphylococcus aureus. Alpha-3D is also three times larger than previously synthesized proteins.
"By designing larger proteins, we can make them more stable and thus easier to manipulate," says Walsh. The next step will be to build a specific function into the protein's structure. Currently, Walsh is retooling the surface of alpha-3D to cause it to bind to a variety of hormonal receptors. Natural proteins that do this are expensive to produce and suffer from limited shelf lives. Novel mimics of these proteins may have enhanced stability and potency.
This work was conducted in the Johnson Research Foundation, a funding and research organization within Penn's Department of Biochemistry and Biophysics that concentrates on the study of physics as it applies to medicine.
The University of Pennsylvania Medical Center's sponsored research and training
ranks second in the United States based on grant support from the National
Institutes of Health, the primary funder of biomedical research and training in
the nation -- $201 million in federal fiscal year 1998. In addition, the
institution continued to maintain the largest absolute growth in funding for
research and training among all 125 medical schools in the country since 1991.
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