Interactions causing catalysis are shown by dotted lines. The target substrate is orange, and the magenta groups are varied via computer to discover mutants that improve conversion. Source: Hein Wijma/University of Groningen

After biotechnologists in the Netherlands taught a computer how to redesign an enzyme into a specific type of chemical catalyst, their colleagues in China used it to produce large quantities of very pure pharmaceutical building blocks.

As natural catalysts that work under mild conditions, enzymes are an attractive alternative to uncatalyzed chemical reactions that often require energy-consuming high temperatures or pressure. Those reactions also may require the use of solvents, or generate toxic side products.

The reason that enzymes aren’t used more often, however, is that the range of reactions they can catalyze is limited. “That's why a lot of effort is being put into modifying natural enzymes,” explained Dick Janssen, a professor of chemical biotechnology at the Groningen Biomolecular and Biotechnology Institute (GBB).

Thus far, it has been a work-intensive proposition. “Proteins are made of 20 different amino acids,” explained Hein Wijma, an expert in molecular design software who did most of the computational work in the study. “If you want to change an enzyme in four positions, there are 20 options for each of them. That results in a huge matrix of protein structures.”

Enter a very fast Monte Carlo search algorithm, which speeds up the discovery of the right outcome by looking for trends in the enzyme's reactivity. In their proof-of-principle study, the team describes four different conversions made by adding ammonium to their selected enzyme, aspartase. Each conversion resulted in around 100 promising “mutant” enzymes, which were ultimately boiled down to around five to 20 that got made in the lab and tested.

The successful mutants were tested in a scaled-up setting by Professor Bian Wu, a colleague in China. “He showed which candidates could produce large quantities of the required product,” said Janssen. Substrate conversions were achieved in quantities up to a kilogram, meaning that enzymes predicted by the researchers’ computation methods appear suitable for use in an industrial setting.

The research appears in the May 21, 2018, edition of Nature Chemical Biology.