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Computer-Based Strategy Designed for Protein Nanomachines

By LabMedica International staff writers
Posted on 09 Jan 2019
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Image: Proteins designed in the lab can now zip together in much the same way that DNA molecules zip up to form a double helix. The technique could enable the design of protein nanomachines that can potentially help diagnose and treat disease, allow for the more exact engineering of cells, and perform a wide variety of other tasks (Photo courtesy of the Institute for Protein Design, University of Washington).
Image: Proteins designed in the lab can now zip together in much the same way that DNA molecules zip up to form a double helix. The technique could enable the design of protein nanomachines that can potentially help diagnose and treat disease, allow for the more exact engineering of cells, and perform a wide variety of other tasks (Photo courtesy of the Institute for Protein Design, University of Washington).
A team of bio-molecular engineers used the Rosetta software suite to design orthogonal protein heterodimers, which are protein "nanomachines" that are expected to enable sophisticated protein-based control logic for synthetic biology applications.

In chemistry and biochemistry, an orthogonal interaction occurs when there are two pairs of substances and each substance can interact with their respective partner, but does not interact with either substance of the other pair. For example, DNA has two orthogonal pairs: cytosine and guanine form a base-pair, and adenine and thymine form another base-pair, but other base-pair combinations are strongly disfavored.

Development of the Rosetta software began in the laboratory of Dr. David Baker at the University of Washington (Seattle, USA) as a structure prediction tool but since then has been adapted to solve common computational macromolecular problems. The Rosetta software suite includes algorithms for computational modeling and analysis of protein structures. It has enabled notable scientific advances in computational biology, including de novo protein design, enzyme design, ligand docking, and structure prediction of biological macromolecules and macromolecular complexes.

Investigators at the University of Washington reported in the December 19, 2018, online edition of the journal Nature that protein–protein interaction specificity could be achieved using extensive and modular side-chain hydrogen-bond networks. They produced millions of four-helix backbones with varying degrees of supercoiling around a central axis, identified those accommodating extensive hydrogen-bond networks, and used Rosetta to connect pairs of helices with short loops and to optimize the remainder of the sequence. Of 97 such designs expressed in Escherichia coli, 65 formed constitutive heterodimers, and the crystal structures of four designs were in close agreement with the computational models and confirmed the designed hydrogen-bond networks.

"This is a first-of-its-kind breakthrough," said first author Zibo Chen, a graduate researcher in biochemistry at the University of Washington. "What we are doing is computationally designing these hydrogen-bond networks so that each protein pair has a unique complementary sequence. There is only one way for them to come together and they do not cross-react with proteins from other pairs."

"Engineering cells to do new tasks is the future of medicine and biotechnology, whether that is engineering bacteria to make energy or clean up toxic waste or creating immune cells that attack cancers," said contributing author Dr. Scott Boyken, a postdoctoral researcher at the institute for protein design at the University of Washington. "This technique provides scientists a precise, programmable way to control how protein machines interact, a key step towards achieving these new tasks. We have opened a major door to protein nanomaterial design."

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