nature biotechnology advance online publication
l e t t e r s
Computational enzyme design holds promise for the production
of renewable fuels, drugs and chemicals. De novo enzyme
design has generated catalysts for several reactions, but with
lower catalytic efficiencies than naturally occurring enzymes14.
Here we report the use of game-driven crowdsourcing to
enhance the activity of a computationally designed enzyme
through the functional remodeling of its structure. Players
of the online game Foldit5,6 were challenged to remodel the
backbone of a computationally designed bimolecular Diels-
Alderase3 to enable additional interactions with substrates.
Several iterations of design and characterization generated
a 24-residue helix-turn-helix motif, including a 13-residue
insertion, that increased enzyme activity >18-fold. X-ray
crystallography showed that the large insertion adopts a
helix-turn-helix structure positioned as in the Foldit model.
These results demonstrate that human creativity can extend
beyond the macroscopic challenges encountered in everyday