H. Gradišar et al., Nature Chemical Biology, Advance Online Publication (April 2013)

Self-assembly required. Specially designed proteins spontaneously assemble into 3D tetrahedra, seen here in both a 2D transmission electron microscope image (left) and a computer simulation (right).

How to Turn a Protein Into a Pyramid

Robert F. Service
2013-04-28 13:00
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Nanotechnologists with a creative streak have turned proteins into origami, folding the biomolecules into relatively complex 3D objects such as a triangular pyramid or tetrahedron. The advance could offer researchers a new way to craft useful nanoscale objects for a variety of functions, such as delivering drugs and making novel catalysts capable of carrying out specific chemical reactions in sequence, much the way organisms do to create the myriad compounds that they rely on.

Designing nano-sized objects from biomolecules hasn't been easy. Previously, researchers had worked mostly with DNA, and it took them more than 3 decades to go from linking a few strands of DNA together into simple triangles and squares to constructing more complex 3D pyramids and cubes. In 2006, scientists in California came up with a major breakthrough when they invented a technique called DNA origami, in which they designed a long strand of DNA to fold back and forth upon itself, eventually assembling into virtually any shape they designed into the DNA from the start, such as a smiley face or sphere.

However, the rules that govern how the strings of amino acids that make up proteins fold are far more complex, says Roman Jerala, a chemist at the National Institute of Chemistry in Ljubljana. Typically, amino acid chains twist into one of several initial shapes like the coil of a telephone cord or sheetlike arrangements. Chemical groups on these coils and sheets then attract and repel one another, forcing the overall protein to adopt a specific 3D shape like a barrel or a fan. Computational biochemists have spent decades trying to tease out these folding rules, in part to design novel proteins from scratch. But the large number of weak chemical interactions continues to make the task very difficult.

Protein nanotechnologists have recently found a way to simplify the problem. For example, researchers led by Derek Woolfson at the University of Bristol in the United Kingdom created a series of precisely designed protein fragments called peptides, each of which spontaneously assembles into a 2D coil with well known properties of how they bind to one another. When placed together in solution, these coils were designed to assemble together into simple 3D spheres that themselves then assemble into an array of hexagonal cages, as the researchers reported earlier this month in Science.

The new work from Jerala's group in Slovenia, reported online today in Nature Chemical Biology, goes one step further. In this case, the Slovenia-led team created a protein origami version of the technology, similar to the previous DNA origami advance. They engineered single long proteins, each of which contained 12 shorter sections, with an amino acid "hinge" in between each pair of sections. Like the U.K. effort, each section was engineered to wind up into a 2D coil with well understood binding properties. When the entire protein was then placed in solution, pairs of the coils in different parts of the long protein were coded so that the weak interactions between amino acids in the coils would draw them together.

The overall result was that the 12-section proteins spontaneously assembled into tetrahedra—geometric shapes made up of four triangle faces (see image). What is more, Jerala says that the approach should be able to make far more complex shapes by rearranging and adding novel peptide sections into their proteins. "The sky is the limit," Jerala says. Because proteins can contain 20 different amino acids—each of which can serve as a unique chemical handle to attach other compounds—researchers may be able to assemble novel structures. One possibility, Jerala says, is to create arrays of nanoscale containers, each of which carries out a separate chemical reaction, with the output of one reaction serving as the starting material for the next. Organisms make extensive use of such chemical assembly lines, a feat chemists have struggled to duplicate.

The work by both the U.K.- and Slovenia-led teams is "fantastic," says Hendrik Dietz, a DNA nanotechnology expert at the Technical University of Munich in Germany. Protein nanostructures might eventually prove easier to modify than their DNA analogs, he says. That's because it should be far easier to link additional proteins to protein origami structures than DNA origami designs, Dietz says. That may eventually make it possible to engineer things like new data storage devices and other electronic materials that require the precise atomic ordering. That hasn't happened yet. But you can bet that nanotechnologists will be racing to put biology's workhorse molecules to work.

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