期刊
ACS SYNTHETIC BIOLOGY
卷 1, 期 4, 页码 130-138出版社
AMER CHEMICAL SOC
DOI: 10.1021/sb200018e
关键词
protein design; binary code; small molecule microarray; four helix bundle; molecular evolution
资金
- NSF [MCB-0817651, MCB-1050510]
- NCI Initiative for Chemical Genetics [N01-CO-12400]
- Machiah Foundation [20070117]
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1050510] Funding Source: National Science Foundation
The availability of large collections of de nova designed proteins presents new opportunities to harness novel macromolecules for synthetic biological functions. Many of these new functions will require binding to small molecules. Is the ability to bind small molecules a property that arises only in response to biological selection or computational design? Or alternatively, is small molecule binding a property of folded proteins that occurs readily amidst colections of unevolved sequences? These questions can be addressed by assessing the binding potential of de nova proteins that are designed to fold into stable structures, but are naive in the sense that they (i) share no significant sequence similarity with natural proteins and (ii) were neither selected nor designed to bind small molecules. We chose three naive proteins from a library of sequences designed to fold into 4-helix bundles and screened for binding to 10,000 compounds displayed on small molecule microarrays. Several binders were identified, and binding was characterized by a series of biophysical assays. Surprisingly, despite the similarity of the three de nova proteins to one another, they exhibit selective ligand binding. These findings demonstrate the potential of novel proteins for molecular recognition and have significant implications for a range of applications in synthetic biology.
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