Like houses, proteins need nails and screws to keep their shape, especially under trying conditions such as extreme heat. Now, by toughening up a typical protein, researchers have figured out the key fasteners that hold a protein together.
The bonds that prop proteins into their three-dimensional structure are the stuff of chemistry textbooks: electrostatic interactions from positively and negatively charged amino acids, hydrophobic entanglements of nonpolar amino acids that prefer similar company, and other more tenuous fasteners. Understanding which of these best stabilizes protein structure would help researchers design longer lasting drugs or even better soap suds. But chemists have been confounded. It's fiendishly difficult to figure out which fasteners build the framework of the protein and which secure the rigging, because every amino acid in a protein interacts with others in a vast network of attractions and repulsions.
A team led by protein chemist Franz Schmid of the University of Bayreuth in Germany simplified the problem. They used two bacterial proteins to tease apart one protein's critical connections. One bacterial species prefers tepid water and the other thrives close to the boiling point. The two proteins share all but 12 amino acids.
By tinkering with the bonds that these dozen contribute to, the researchers determined that one electrostatic interaction and one hydrophobic interaction help the proteins handle hot water. Change the amino acids that make these bonds, they report in the May issue of Nature Structural Biology, and the protein melts in the heat. But add those interactions to the mild protein, and it can withstand temperatures up to 28°C higher than normal. "It's very simple to make a good protein bad," Schmid says, but more challenging to retrofit a weak one.
"It's a nice, clear-cut answer" to the question of how some proteins are sturdier in heat and other harsh environments, says biochemist C. Nick Pace of Texas A&M University in College Station. This finding, along with a few other papers last year, emphasizes the importance of electrostatic interactions for protein stability, he says, and will enable protein chemists to create more stable protein-based drugs.