They have designed and successfully synthesized a variant of a protein that nature uses to manufacture the essential amino acid histidine. It is more than twice the size of the previous record holder, a protein created by researchers at the University of Washington in 2003.
Recently, protein engineers have verified a potential treatment strategy for HIV by using designed protein vaccines in mice and have designed artificial proteins that mimic antibodies in broadly neutralizing flu infections. The technique developed at Vanderbilt promises to expand the scope of these efforts substantially.
Imagine making a necklace 10 beads long with beads that come in 20 different colors. There are more than 10 trillion different combinations to choose among. This provides an idea of the complexity involved in designing novel proteins. For a protein of a given size, the modeling software creates millions of versions by putting each amino acid in every position and evaluating the stability of the resulting molecule. This takes a tremendous amount of computing power which skyrockets as the length of the protein increases.
“The current limit of this approach, even using the fastest supercomputers, is about 120 amino acids,” said Meiler. The previous record holder contained 106 amino acids. The newly designed protein contains 242 amino acids. The Vanderbilt group got around this limit by modifying the widely used protein engineering platform called ROSETTA so that it can incorporate symmetry in the design process.
The paper reporting this achievement appears in the Nov. 16 issue of the Journal of American Chemical Society and is available online. Members of Meiler’s team are research assistant Carie Fortenberry, undergraduate students Elizabeth Bowman, Will Proffitt, and Brent Dorr and research assistant professors of biochemistry Joel Harp and Laura Mizoue. The research was supported by grants from the Defense Advanced Research Projects Agency’s protein design project and the National Science Foundation.
David F. Salisbury | Vanderbilt University
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