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A de novo protein from a designed combinatorial library of amino acid sequences has for the first time been shown to fold up compactly, just like a natural protein. The work suggests that such libraries could be sources of nativelike designed proteins with potentially novel functions. JUST RIGHT NMR solution structure of four-helix bundle protein shows it adopts structure designed into the combinatorial library from which it was obtained. REPRINTED WITH PERMISSION FROM PNAS It’s been known for some time that combinatorial amino acid sequence libraries with sequence patterns similar to those of native proteins can generate appreciable numbers of foldable structures. Michael H. Hecht and coworkers at Princeton University use libraries with binary patterning (specific patterns of polar and nonpolar residues) in an effort to generate proteins with nativelike structures—abundant -helices and/or -strands, most hydrophobic residues buried in the interior, and most hydrophilic residues exposed externally to solvent. The researchers have identified a number of useful proteins in such libraries, including cofactor-binding proteins and enzyme-like catalysts. But they were never able to obtain crystal or NMR structures of these proteins, suggesting that the proteins could not fold properly and weren’t truly like natural proteins. Hecht, Jean Baum of Rutgers University, and coworkers have now determined the NMR structure of a protein from a binary-patterned 102-unit sequence library. The protein is a four-helix bundle—the type of structure specified by the design of the library [Proc. Natl. Acad. Sci. USA, 100, 13270 (2003)]. The work is “a major step forward,” comments William F. DeGrado of the University of Pennsylvania School of Medicine. It suggests, he says, “that consideration of binary patterning alone can give rise to a large number of natively folded structures—assuming the template is carefully chosen.” |
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