Nature's Recipe for Proteins: Can We Expand its Vocabulary?

Thursday - January 25 2024, 11:58 UTC - 10 months ago

A recent study has successfully incorporated four new exotic amino acids into bacterial proteins, opening the door to potentially expand the capabilities of proteins in fields such as medicine and biotechnology. These exotic amino acids could also play a role in environmental sustainability, especially in the manufacturing of biofuels. However, adding these new amino acids into living cells is a difficult task, but a team of researchers has found a solution by identifying two new molecular vertices that can bond with them and potentially work better than the current components used in protein synthesis.

Nature has a set recipe for making proteins. Triplets of DNA letters translate into 20 molecules called amino acids. These basic building blocks are then variously strung together into the dizzying array of proteins that make up all living things. Proteins form body tissues, revitalize them when damaged, and direct the intricate processes keeping our bodies’ inner workings running like well-oiled machines.

Studying the structure and activity of proteins can shed light on disease, propel drug development, and help us understand complex biological processes, such as those at work in the brain or aging. Proteins are becoming essential in non-biological contexts too, like for example, in the manufacturing of climate-friendly biofuels.

Yet with only 20 molecular building blocks, evolution essentially put a limit on what proteins can do. So, what if we could expand nature’s vocabulary? .

By engineering new amino acids not seen in nature and incorporating them into living cells, exotic proteins could do more. For example, adding synthetic amino acids to protein-based drugs—such as those for immunotherapy—could slightly tweak their structure so they last longer in the body and are more effective. Novel proteins also open the door to new chemical reactions that chew up plastics or more easily degradable materials with different properties.

But there’s a problem. Exotic amino acids aren’t always compatible with a cell’s machinery.

A new study in Nature, led by synthetic biology expert Dr. Jason Chin at the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK, brought the dream a bit closer. Using a newly developed molecular screen, they found and inserted four exotic amino acids into a protein inside bacteria cells. An industrial favorite for churning out insulin and other protein-based medications, the bacteria readily accepted the exotic building blocks as their own.

All the newly added components are different from the cell’s natural ones, meaning the additions didn’t interfere with the cell’s normal functions.

"It’s a big accomplishment to get these new categories of amino acids into proteins," Dr. Chang Liu at the University of California, Irvine who was not part of the study, told Science.

A Synthetic Deadlock .

Adding exotic amino acids into a living thing is a nightmare.

Picture the cell as a city, with multiple "districts" performing their own functions. The nucleus, shaped like the pit of an apricot, houses our genetic blueprint recorded in DNA. Outside the nucleus, protein-making factories called ribosomes churn away. Meanwhile, RNA messengers buzz between the two like high-speed trains shuttling genetic information to be made into proteins.

Like DNA, RNA has four molecular letters. Each three-letter combination forms a "word" encoding an amino acid. The ribosome reads each word and summons the associated amino acid to the factory using transfer RNA (tRNA) molecules to grab onto them.

The tRNA molecules are tailormade to pick up particular amino acids with a kind of highly specific protein "glue." Once shuttled into the ribosome, the amino acid is plucked off its carrier molecule a little like a bucket off a crane. The ribosome then slides the amino acid next to another amino acid, stitching them together in a precise sequence.

With such a complex import process, how can we easily fit in exotic amino acids with perhaps an entirely different supporting "glue"? .

This is where Dr. Chin’s team comes in with a sleek solution.

The researchers found two new vertices that can bond amino acids together: a group of molecules with technical sounding names like N3H2Q, E5B, T3L, F61A8, and C45V. The hope is that these new vertices will be "friendlier" with exotic sides, more than the cell components currently used to piece together proteins, called amino acid residues.

To test in the lab, the team made synthetic tRNA molecules equipped with the new friendlier vertices to lure their preferred amino acid targets. Each unique tRNA carried one of the four exotic amino acids on its traveler’s check.