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De novo design of a four-fold symmetric TIM-barrel protein with atomic-level accuracy

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)29-34
Number of pages6
JournalNature Chemical Biology
Issue number1
Early online date23 Nov 2015
DateAccepted/In press - 7 Oct 2015
DateE-pub ahead of print - 23 Nov 2015
DatePublished (current) - Jan 2016


Despite efforts for over 25 years, de novo protein design has not succeeded in achieving the TIM-barrel fold. Here we describe the computational design of four-fold symmetrical (β/α)8 barrels guided by geometrical and chemical principles. Experimental characterization of 33 designs revealed the importance of side chain-backbone hydrogen bonds for defining the strand register between repeat units. The X-ray crystal structure of a designed thermostable 184-residue protein is nearly identical to that of the designed TIM-barrel model. PSI-BLAST searches do not identify sequence similarities to known TIM-barrel proteins, and sensitive profile-profile searches indicate that the design sequence is distant from other naturally occurring TIM-barrel superfamilies, suggesting that Nature has sampled only a subset of the sequence space available to the TIM-barrel fold. The ability to design TIM barrels de novo opens new possibilities for custom-made enzymes.

    Structured keywords

  • Bristol BioDesign Institute

    Research areas

  • Circular Dichroism, Crystallography, X-Ray, Hydrogen Bonding, Models, Molecular, Protein Conformation, Protein Engineering, Protein Folding, Proteins, Chemical genetics, Target identification, Target validation, synthetic biology

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    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via Nature at Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 2.8 MB, PDF document


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