Issue Date: March 19, 2018 | Web Date: March 18, 2018
Polymer chain wraps up proteins to keep them stable
A new random heteropolymer with mixed hydrophilic and hydrophobic groups coats proteins to help them remain folded and active in environments that would normally unfold and inactivate them (Science 2018, DOI: 10.1126/science.aao0335).
Random heteropolymers have been designed before to enhance the properties of small molecules, but not proteins. And researchers have previously enhanced protein stability by incorporating proteins in micelles or sol-gel networks or by combining proteins with polyelectrolytes and other polymers. But the new heteropolymer preserves native protein function and structure more faithfully in both aqueous and organic media, say Ting Xu of the University of California, Berkeley, and coworkers, who developed it. The heteropolymer could have bioremediation applications and allow researchers to make proteins without the help of cells.
“This is outstanding work showing the ability of functionally diverse, random copolymers to act as chaperones and protein stabilizers for diverse applications,” says William DeGrado of the University of California, San Francisco. “Overall, it is a significant advance for polymer chemists and protein scientists alike.”
To develop the polymer, Xu and coworkers first analyzed statistical distributions of the size and separation of hydrophobic, uncharged hydrophilic, and charged hydrophilic patches found on protein surfaces. They then made heteropolymers consisting of random arrangements of four types of methacrylate monomers. Each monomer can interact with a different protein-surface patch: methyl methacrylate and 2-ethylhexyl methacrylate bind hydrophobic spots, oligo(ethylene glycol)methacrylate recognizes uncharged hydrophilic sites, and 3-sulfopropyl methacrylate potassium salt interacts with positively charged hydrophilic regions. The researchers tested different ratios of the four monomers to find one that worked best at preserving native structure and function of different proteins in non-native environments.
In one demonstration of the polymer’s abilities, Xu and coworkers synthesized a membrane protein in aqueous solution that normally can be produced only in cells, where it can fold properly and has access to the hydrophobic membrane environment. The heteropolymer surrounded the protein as it was synthesized and helped it fold. The polymer-bound protein also functioned normally when transferred to membrane vesicles.
The versatile and economical approach could facilitate expressing a wide variety of proteins in cell-free systems, says Jeffery Saven of the University of Pennsylvania. “Membrane proteins are a large fraction of the human genome and the majority of all drug targets,” he says. “Expressing them in a workable form is often the bottleneck to further study.”
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