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Major nanotechnology milestone: protein catalysts designed for non-natural chemical reactions

A major milestone along the protein design path to productive nanosytems and advanced nanotechnology has been achieved—the design by computational methods of enzymes that catalyze reactions for which biological enzymes do not exist. The team that achieved this nanotech milestone includes Prof. David Baker, who shared the 2004 Foresight Institute Feynman Prize in Nanotechnology in the Theoretical category, and who was subsequently elected to the US National Academy of Sciences. From a UCLA press release written by Stuart Wolpert “‘Designer enzymes’ created by chemists at UCLA, U. of Washington“:

Chemists from UCLA and the University of Washington have succeeded in creating “designer enzymes,” a major milestone in computational chemistry and protein engineering.

The research, by a UCLA chemistry group led by professor Kendall Houk and a Washington group headed by biochemist David Baker, is reported March 19 in the advance online publication of the journal Nature. The Defense Advanced Research Projects Agency (DARPA) supported the study.

…”The design of new enzymes for reactions not normally catalyzed in nature is finally feasible,” Houk said. “The goal of our research is to use computational methods to design the arrangement of groups inside a protein to cause any desired reaction to occur.”

“Enzymes are such potent catalysts; we want to harness that catalytic ability,” said research co-author Jason DeChancie, an advanced UCLA chemistry graduate student working with Houk’s group. “We want to design enzymes for reactions that naturally occurring enzymes don’t do. There are limits on the reactions that natural enzymes carry out, compared with what we can dream up that enzymes can potentially do.”

Combining chemistry, mathematics and physics, the scientists report in the Nature paper that they have successfully created designer enzymes for a chemical reaction known as the Kemp elimination, a non-natural chemical transformation in which hydrogen is pulled off a carbon atom.

In a previous paper, published in the journal Science on March 7, the chemists reported another successful chemical reaction that uses designer enzymes to catalyze a retro-aldol reaction, which involves breaking a carbon-carbon bond. The aldol reaction is a key process in living organisms associated with the processing and synthesis of carbohydrates. This reaction is also widely used in the large-scale production of commodity chemicals and in the pharmaceutical industry, Houk said.

…Houk and Baker’s research groups have worked together for three years. Using algorithms and supercomputers, the UCLA chemists design the active site for the enzymes — the area of the enzymes in which the chemical reactions take place — and give a blueprint for the active site to their University of Washington colleagues. Baker and his group then use their computer programs to design a sequence of amino acids that fold to produce an active site like the one designed by Houk’s group; Baker’s group produces the enzymes.

How far off are designer enzymes with important applications?

“I think we’re there,” DeChancie said. “These papers are showing the technology is now in place.”

The Nature paper (abstract) reports the design of catalysts for a reaction for which no biological catalyst exists. The Science paper published a few weeks ago (abstract) reports the design of catalysts for a type of reaction that happens in living organisms, but working on a molecule (the substrate) that does not occur in biological systems. Although the press release does not explicitly mention nanotechnology, the design of artificial catalysts to remove hydrogen atoms bonded to carbon atoms and to break carbon-carbon bonds should be of some utility for atomically precise manufacturing. Furthermore, the authors expect to be able to make a very wide range of catalysts beyond those that exist in nature. Among their conclusions in the Nature paper:

The computational methodology described here can be readily generalized to design catalysts for more complex multistep reactions. The combination of computational enzyme design to create the overall active site framework for catalysing a synthetic chemical reaction with molecular evolution to fine-tune and incorporate subtleties not yet modelled in the design methodology is a powerful route to create new enzyme catalysts for the very wide range of chemical reactions for which naturally occurring enzymes do not exist.

—Jim

4 Responses to “Major nanotechnology milestone: protein catalysts designed for non-natural chemical reactions”

  1. Christine Peterson Says:

    Probably not too many people realize it yet, but this is very exciting work! —Christine

  2. Dale Amon Says:

    This is huge.

  3. Ashley Cameron Says:

    A profound advance in technology which has so many applications. I hope to read more papers about this in the future.

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