For more than 25 years, chemists around the world have been trying to reach the elusive goal of creating proteins that catalyze reactions not found in nature.
Last month, chemists from Duke and the University of California, San Francisco published their research that advances the creation of a functional synthetic enzyme. This synthesized enzyme is a protein that binds tightly with porphyrin, a molecule that can act as a non-biological catalyst.
“When you shake somebody’s hand, it’s the worst ever when the person doesn’t grip back, right? But that is exactly how people have been designing proteins that bind to small molecules for the past couple decades," said Nicholas Polizzi, a postdoctoral researcher at UCSF and former graduate student at Duke. "People have only been focusing on the parts of the protein that touch the small molecule. In this case, it’s the 'fingers' of the dead-fish handshake.”
Protein enzymes lower the energy required to make many of life's reactions to take place and are considered essential for any organism. They often pair with cofactors, which are metals or smaller molecules that can hold certain molecules in a position to cause a chemical reaction.
In addition to their activity inside cells, they can also be used externally for research for other controlled processes, inspiring researchers like Polizzi and his team to study their function.
Polizzi continued his handshake analogy, noting that it takes more than just fingers to make a solid handshake. Forearm muscles need to be engaged to establish a firm grip, he said.
Similarly, the 3D structure of an enzyme is comprised of parts that directly interact with other molecules in conjunction with parts farther away that provide grip strength.
Polizzi said that he and his team designed their synthetic protein in a similar fashion to the two-part handshake model. They accounted for how proteins like to fold into tight little globs, with their oily parts wrapped up safely in the interior. The researchers also computationally designed the entire 3D protein structure so that when it would bind with the molecule porphyrin, the protein could finish folding and provide the energy needed to wrap securely around porphyrin.
At the moment, the newly synthesized protein binds too tightly to porphyrin to catalyze a reaction and needs to be more flexible to reach its full potential.
However, with a few changes, Polizzi said he thinks that the protein will eventually reach the ultimate goal of catalyzing a reaction with the help of cofactor porphyrin. He and his team are currently exploring designing and testing such modifications toward this aim.
Polizzi added that their research could have applications across diverse fields such as chemistry, medicine and environmental science.
If synthesizing enzymes and proteins becomes a well-understood, well-utilized methodology, it would be possible to use synthesized proteins as models to better learn about natural proteins, he explained. Synthetic enzymes could also be turned into small molecule sensors, useful in surgery and environmental cleanup. Additionally, a new class of synthetic proteins might be harnessed for the specialized delivery of medicinal drugs with diseases like cancer to maximize treatment.
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