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De novo computational design of retro-aldol enzymes

Academic Article
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Overview

authors

  • Jiang, L.
  • Althoff, E. A.
  • Clemente, F. R.
  • Doyle, L.
  • Rothlisberger, D.
  • Zanghellini, A.
  • Gallaher, J. L.
  • Betker, J. L.
  • Tanaka, F.
  • Barbas III, Carlos
  • Hilvert, Donald M.
  • Houk, K. N.
  • Stoddard, B. L.
  • Baker, D.

publication date

  • March 2008

journal

  • Science  Journal

abstract

  • The creation of enzymes capable of catalyzing any desired chemical reaction is a grand challenge for computational protein design. Using new algorithms that rely on hashing techniques to construct active sites for multistep reactions, we designed retro-aldolases that use four different catalytic motifs to catalyze the breaking of a carbon-carbon bond in a nonnatural substrate. Of the 72 designs that were experimentally characterized, 32, spanning a range of protein folds, had detectable retro-aldolase activity. Designs that used an explicit water molecule to mediate proton shuffling were significantly more successful, with rate accelerations of up to four orders of magnitude and multiple turnovers, than those involving charged side-chain networks. The atomic accuracy of the design process was confirmed by the x-ray crystal structure of active designs embedded in two protein scaffolds, both of which were nearly superimposable on the design model.

subject areas

  • Aldehyde-Lyases
  • Algorithms
  • Binding Sites
  • Catalysis
  • Catalytic Domain
  • Computer Simulation
  • Crystallography, X-Ray
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Kinetics
  • Models, Molecular
  • Protein Conformation
  • Protein Engineering
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Identity

PubMed Central ID

  • PMC3431203

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.1152692

PubMed ID

  • 18323453
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Additional Document Info

start page

  • 1387

end page

  • 1391

volume

  • 319

issue

  • 5868

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