Proteins from an unevolved library of de novo designed sequences bind a range of small molecules

Izhack Cherny, Maria Korolev, Angela N. Koehler, Michael H. Hecht

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


The availability of large collections of de novo 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 collections of unevolved sequences? These questions can be addressed by assessing the binding potential of de novo proteins that are designed to fold into stable structures, but are "naivë" 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 naivë 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 novo 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.

Original languageEnglish (US)
Pages (from-to)130-138
Number of pages9
JournalACS Synthetic Biology
Issue number4
StatePublished - Apr 20 2012

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Biomedical Engineering


  • Binary code
  • Four helix bundle
  • Molecular evolution
  • Protein design
  • Small molecule microarray


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