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Proteins designed ‘from scratch’ function in living cells

There is a substantial area of overlap between the new field of synthetic biology and the protein design path to advanced nanotechnology. Nearly two years ago we pointed to an important milestone on the protein design path: “Protein design revolution points toward advanced nanotechnology“. Now, with nods to Science Daily and to KurzweilAI, we learn of another “groundbreaking achievement” along this path: “Princeton scientists construct synthetic proteins that sustain life“:

In a groundbreaking achievement that could help scientists “build” new biological systems, Princeton University scientists have constructed for the first time artificial proteins that enable the growth of living cells.

The team of researchers created genetic sequences never before seen in nature, and the scientists showed that they can produce substances that sustain life in cells almost as readily as proteins produced by nature’s own toolkit.

“What we have here are molecular machines that function quite well within a living organism even though they were designed from scratch and expressed from artificial genes,” said Michael Hecht, a professor of chemistry at Princeton, who led the research. “This tells us that the molecular parts kit for life need not be limited to parts — genes and proteins — that already exist in nature.”

The work, Hecht said, represents a significant advance in synthetic biology, an emerging area of research in which scientists work to design and fabricate biological components and systems that do not already exist in the natural world. One of the field’s goals is to develop an entirely artificial genome composed of unique patterns of chemicals.

“Our work suggests,” Hecht said, “that the construction of artificial genomes capable of sustaining cell life may be within reach.”

The research “De novo designed proteins from a library of artificial sequences function in Escherichia coli and enable cell growth” was published in the Open Access journal Public Library of Science ONE.

The amazing result here is that the researchers took a library of about 1.5 million novel 102-residue sequences that had been designed to fold into stable 4-helix bundles, but not to mimic any specific natural proteins, and found that this library of designed proteins rescued the growth of each of four bacterial strains lacking a gene necessary for growth. A total of 18 artificial sequences compensated for the loss of four natural genes. The fact that this strategy worked for four out of 27 mutant strains tested shows that a library of sequences designed only to form stable structures gives an unevolved, unnatural protein that can substitute functionally for a natural one at a relatively high frequency. Since the bacterial genome contains about 4000 genes, about 0.1 per cent of the genome can be replaced by artificial genes designed from scratch. Furthermore, in all four cases, the artificial proteins were much smaller and simpler in structure than the natural proteins they functionally replaced, although they were less active (the rescued cells grew more slowly than cells with the natural protein intact).

The connection that I see between this advance in synthetic biology and the development of molecular manufacturing is (1) the demonstration that the sequence space of functional proteins is much larger than the universe of evolved biological sequences, and (2) that functional proteins can be smaller and simpler in structure than evolved proteins implementing the same functions.

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