Will the future of chemical manufacturing be smaller, faster and greener? Major advances from researchers at UC Santa Barbara (UCSF), UC Santa Barbara (UCSF) and the University of Pittsburgh do propose this.
In a scientifically published study, the team developed a revolutionary workflow for designing enzymes from scratch, rather than modifying existing ones. These custom catalysts can transform drug development, materials science and industrial chemistry by enabling more efficient, selective and environmentally friendly processes.
“If people can design very effective enzymes from scratch, you can solve many important problems,” said Professor Yang Yang Yang, senior author of the paper.
Build better catalysts through design
The innovative approach focuses on creating “detoot” proteins, which are new enzymes built from amino acid building blocks, rather than modified versions of existing proteins. The team specializes in reactions where natural enzymes perform poorly or do not exist at all.
These customized design enzymes, nicknamed “novochromes”, have extraordinary abilities:
*Create carbon and carbon-silicon bonds accurately
*Operate at temperatures up to 100°C
* Stay stable in an environment containing up to 70% organic solvent
*Working faster than highly evolved natural enzymes
*Although small in size, it remains highly selective
“For basic research, chemists and biologists have long wanted to be able to design enzymes from scratch,” Yang noted.
Design process: AI conforms to chemical intuition
How does a person build enzymes from nothing? The team started with a simple spirobranch protein as a framework. They then adopted cutting-edge AI methods to design specific sequences of amino acids that translate this basic structure into a powerful catalyst.
However, this process is not simple. The initial design showed promise but lacked optimal performance.
“The earlier variants are reasonable catalysts, but not the best ones, because the efficiency and selectivity are moderate,” Young explained.
After analyzing its initial design using X-ray crystallography, the researchers identified a structural defect, a “chaotic cycle” that needs to be refined. This shows that even with advanced AI tools, human expertise remains crucial.
“In other words, while AI-based protein design methods are very useful, to have a very good catalyst, we still have to do everything the right way with internal algorithms and our chemical intuition,” Yang said.
Record performance
The exquisite design process leads to enzymes with impressive capabilities. A novochromes variant has a business frequency of 290,000 reactions per hour, which coincides with billions of years of evolution of natural enzymes.
Engineered enzymes maintain excellent performance when tested on a variety of substrates with different structures. A particularly noteworthy achievement was the creation of cyclopropane with adjacent fourth-level stereocenter, a molecular arrangement important in drug development.
Evolution satisfies design
The team also demonstrated that its artificial enzymes can be further improved through directional evolution – the process of introducing mutations and selecting the most efficient variants.
Through this process, they created an enzyme that can form carbon-silicon bonds at unprecedented efficiency. The number of evolutionary enzymes turned over 32,990, exceeding the previous catalysts for the same reaction.
Molecular simulations reveal the secret to this improved performance: Evolved enzymes have more rigid, pre-organized active sites that put the reacting molecule in the optimal position.
Interestingly, a bond mutation involves the introduction of a helix line of proline, an amino acid that usually destroys the helix structure. This counterintuitive change helps the enzyme better match the profile of its substrate.
The Green Chemistry Future
In addition to its impressive catalytic capacity, these enzymes offer significant environmental benefits. Traditional chemical manufacturing usually relies on toxic solvents, dangerous metals and harsh conditions.
“If you really understand the design principles, you can build protein catalysts to use any cofactor you want to use and achieve the challenging conversion of the greenest solvent in the reaction medium,” Yang said.
This approach may lead to more sustainable chemical processes, which may potentially reduce pollution and energy consumption while increasing efficiency and product purity.
The research team is now exploring how to create simpler, smaller enzymes with similar activities and generate enzymes that run through mechanisms previously unknown in nature.
As this technology develops, we may see a shift in the way pharmaceuticals, materials and other chemicals are manufactured, a change that can benefit industry and the environment.
The research for this study was conducted by Kaipeng Hou, Wei Huang, Miao Qui, Thomas H. Tugwell, Turki Alturaifi, Yuda Chen, Xingjie Zhang, Lei Lu, and Samuel I. Mann.
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