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By adding β- and γ-amino acids to peptides, a research team has shown that it is possible to create structural mimics of α-helices that are more stable and potentially more useful than the natural versions. Peptide helices are often involved in biological signaling. The work could lead to designed peptides that have desirable properties and are resistant to enzymatic degradation.
Chemistry professor Samuel H. Gellman and postdoc Tomohisa Sawada of the University of Wisconsin, Madison, demonstrated the approach by making a 12-amino acid peptide from one β-, one γ-, and 10 conventional α-amino acids (J. Am. Chem. Soc., DOI: 10.1021/ja202175a).
Because β- and γ-amino acids have one and two more backbone atoms than α-amino acids, respectively, the designed peptide has the same number of backbone atoms as a 14 α-amino acid peptide.
The β- and γ-amino acids of the designed peptide contain cyclic groups that make it more likely to fold. "By incorporating small rings in the backbone, which both β- and γ-amino acids allow us to do, we can build in a level of local folding propensity you can't get with α-amino acid residues," Gellman says.
In the new peptide, which has a αγααβα repeating pattern, the α-amino acids align on one side of the helix—a feature that could be useful, for example, where only one helix face docks against another structure.
Gellman and Sawada show that the α/β/γ peptide is stable enough to form the same structure in water and in 50% methanol. "It's already about as folded as it's going to get in water," Gellman says. Water is "the toughest solvent for peptide or protein folding," he notes. It's also the solvent that matters in biological settings.
Identifying "a helix-forming oligomer that not only contains α-, β-, and γ-amino acids but also forms this structure in aqueous solution is very impressive," says André Cobb, who studies peptidomimetics at the University of Reading, England. "The way in which the β and γ units stack on top of each other within the helix gives the structure a stability that will be potentially useful in the design of future peptidomimetics."
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