November 08, 2012

Researchers design proteins from scratch with predictable structures to enable building blocks for nanoscale assembly

Nature - Proteins are an enormous molecular achievement: chains of amino acids that fold spontaneously into a precise conformation, time after time, optimized by evolution for their particular function. Yet given the exponential number of contortions possible for any chain of amino acids, dictating a sequence that will fold into a predictable structure has been a daunting task.

Now researchers report that they can do just that. By following a set of rules described in a paper published in Nature today1, a team from David Baker’s laboratory at the University of Washington in Seattle has designed five proteins from scratch that fold reliably into predicted conformations. In a blind test, the team showed that the synthesized proteins closely match the predicted structures.

“There’s really only one previous example of a protein that has been designed from scratch: that’s Top7 which we designed 10 years ago,” said Baker, a computational structural biologist. “Top7 was sort of a one-off case,” he says. In the new work, the team presents a generalized approach.

“What you have now is a flexible set of building blocks for nanoscale assembly,” says Jeremy England, a molecular biophysicist at the Massachusetts Institute of Technology in Cambridge, who was not involved in the work.

In 1981, Eric Drexler wrote of the protein pathway to molecular manufacturing.

The team developed a number of candidate sequences designed to fold into one of five structures. They vetted these sequences using the group’s Rosetta@home program, which uses volunteers’ home computer power to run protein-folding simulations. Rosetta volunteers test-folded each sequence hundreds of thousands of times. About 10% of the sequences had predicted structures that were stable and matched what the team intended. The winning sequences did not match any known natural proteins.

One might wonder how designing a new protein from scratch could be better than starting with natural proteins, given the head start that nature has in evolving effective functions and stable conformations. In fact, evolution has honed the structures of many proteins so precisely that it can be difficult to get the backbone to budge into another conformation to accommodate a new function, Baker says. “This paper provides the opportunity to design the structure and function at the same time,” says Baker. “Rather than taking an already existing scaffold, now you can design a backbone to order for exactly the function you want to carry out.” That will be the next step — incorporating function into the designs.

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