Study finds new approach for designing proteins

As advances in DNA synthesis technology merge with improvements in computational design of new proteins, the stage is set for a new era of data-driven protein molecular engineering, a study has shown.

Gabriel Rocklin, a post-doctoral fellow in biochemistry at the University of Washington School of Medicine, is the lead author of a paper published in the latest issue of the journal Science on the testing of folding stability for computationally designed proteins, which was made possible by a new high-throughput approach, Xinhua news agency reports.

Made of amino acid chains with specific sequences, proteins are biological workhorses, the report said. These chains fold into three-dimensional conformations as natural protein sequences are encoded in cellular deoxyribonucleic acid (DNA).

The sequence of the amino acids in the chain guides where it will bend and twist, and how parts will interact to hold the structure together.
Researchers have studied these interactions for decades by examining the structures of naturally occurring proteins.

However, natural protein structures are typically large and complex, with thousands of interactions that collectively hold the protein in its folded shape.

In addition, the researchers want to build new molecules, not found naturally, that can perform tasks in preventing or treating disease in industrial applications, in energy production and in environmental cleanups.

"However, computationally designed proteins often fail to form the folded structures that they were designed to have when they are actually tested in the lab," the report quoted Rocklin as saying.

"Still, even simple proteins are so complicated that it was important to study thousands of them to learn why they fold," he added. "This had been impossible until recently, due to the cost of DNA. Each designed protein requires its own customized piece of DNA so that it can be made inside a cell. This has limited previous studies to testing only tens of designs."

In the new study, the researchers tested more than 15,000 newly designed mini-proteins that do not exist in nature to see whether they form folded structures.

Their testing led to the design of 2,788 stable protein structures and could have many bioengineering and synthetic biology applications. Their small size may be advantageous for treating diseases when the drug needs to reach the inside of a cell.

In comparison, major protein design studies in the past few years have generally examined only 50 to 100 designs. To encode their designs of short proteins in this project, the researchers used the DNA oligo library synthesis technology which was originally developed for other laboratory protocols such as­ large gene assembly.

By repeating the cycle of computation and experimental testing over several iterations, they learned from their design failures and progressively improved their modeling. Their design success rate rose from 6 per cent to 47 per cent. They also produced stable proteins in shape where all of their first designs failed.

The authors predict as DNA synthesis technology continues to improve, high-throughput protein design will become possible for larger, more complex protein structures.