Designing Enzymes from Scratch: A Breakthrough in Chemistry

Researchers at UC Santa Barbara, UCSF, and the University of Pittsburgh have made a groundbreaking discovery in chemistry, enabling the design of enzymes from scratch. This breakthrough has far-reaching implications for various fields, including drug development, materials science, and biotechnology.

According to Professor Yang Yang, a senior author on the paper, “If people could design very efficient enzymes from scratch, you could solve many important problems.” De novo enzyme design can overcome limitations in function and stability found in natural catalysts without losing their inherent selectivity and efficiency.

Catalysts, both biological and synthetic, are the backbone of chemistry. They accelerate reactions that change the structures of target molecules. Enzymes, in particular, are “nature’s privileged catalysts” due to their high level of selectivity and efficiency. However, natural enzymes tend to function under narrow conditions, favoring specific molecules and environments.

To address this limitation, scientists have turned to de novo protein design – a bottom-up approach that uses amino acid building blocks to create proteins with specific structures and functions. De novo proteins are relatively small, which provides favorable efficiency relative to most enzymes. They also exhibit excellent thermal and organic solvent stability, allowing for wider temperature ranges and up to 60% of organic solvents.

The researchers demonstrated their proof-of-concept by using de novo protein design to create enzymes that can form carbon-carbon or carbon-silicon bonds – a challenging transformation that requires efficient natural enzymes. They used a helical bundle protein as a framework, which they then modified using state-of-the-art artificial intelligence methods to design sequences of amino acids with the desired functionalities and properties.

The initial results showed reasonable catalysts but not the best due to modest efficiency and selectivity. However, after a second round of design using a loop searching algorithm, four out of 10 designs exhibited high activity and excellent stereoselectivity.

This breakthrough demonstrates that de novo protein design can be a powerful tool in catalysis, offering chemists more efficient and selective reactions as well as products that aren’t easily reached with natural enzymes or small-molecule synthetic catalysts. Further work will involve exploring ways to mimic natural enzyme function with simpler, smaller but equally active de novo enzymes and generating de novo enzymes that operate via mechanisms not previously known in nature.

Research in this paper was conducted by Kaipeng Hou, Wei Huang, Miao Qui, Thomas H. Tugwell, Turki Alturaifi, Yuda Chen, Xingjie Zhang, Lei Lu, and Samuel I. Mann.

A team of researchers from Rice University and Baylor College of Medicine has developed an innovative strategy for identifying toxic compounds in soil, including those that have never been isolated or studied before. The new approach uses machine learning algorithms, theoretical predictions, and light-based imaging techniques to detect polycyclic aromatic hydrocarbons (PAHs) and their derivative compounds (PACs), which are linked to cancer and other serious health problems.

The researchers used surface-enhanced Raman spectroscopy, a light-based imaging technique that analyzes how light interacts with molecules, tracking the unique patterns or spectra they emit. These spectra serve as “chemical fingerprints” for each compound. To refine this method, the team designed signature nanoshells to enhance relevant traits in the spectra.

Using density functional theory, a computational modeling technique, the researchers calculated the spectra of a range of PAHs and PACs based on their molecular structure, generating a virtual library of “fingerprints.” Two complementary machine learning algorithms – characteristic peak extraction and characteristic peak similarity – were then used to parse relevant spectral traits in real-world soil samples and match them to compounds mapped out in the virtual library.

This method addresses a critical gap in environmental monitoring, opening the door to identifying a broader range of hazardous compounds, including those that have changed over time. The researchers tested this approach on soil from a restored watershed and natural area using artificially contaminated samples and a control sample, with results showing the new method reliably picked out even minute traces of PAHs.

The future holds promise for on-site field testing by integrating machine learning algorithms and theoretical spectral libraries with portable Raman devices into mobile systems. This would enable farmers, communities, and environmental agencies to test soil for hazardous compounds without needing to send samples to specialized labs and wait days for results.

The discovery of new medicines is an intricate process that requires patience, precision, and creativity. A research team from the University of Oklahoma has made a groundbreaking breakthrough that could accelerate this process, making it faster, safer, and more cost-effective. Their innovative method allows for the insertion of a single carbon atom into drug molecules at room temperature, opening up new possibilities for chemical diversity without compromising sensitive structures.

Nitrogen atoms and nitrogen-containing rings, known as heterocycles, play a crucial role in medicine development. A team led by OU Presidential Professor Indrajeet Sharma has found a way to modify these rings by adding just one carbon atom using a fast-reacting chemical called sulfenylcarbene. This process, called skeletal editing, transforms existing molecules into new drug candidates.

The significance of this discovery lies in its potential to change the molecule’s biological and pharmacological properties without altering its functionalities. This could unlock uncharted regions of chemical space in drug discovery, making it easier to find effective treatments for various diseases.

Unlike previous studies that relied on potentially explosive reagents and posed significant safety concerns, Sharma’s team has developed a bench-stable reagent that generates sulfenylcarbenes under metal-free conditions at room temperature. This achievement reduces environmental and health risks associated with metal-based carbenes.

The researchers are also exploring how this chemistry could revolutionize DNA-encoded library (DEL) technology, which allows for the rapid screening of billions of small molecules for their potential to bind to disease-relevant proteins. The metal-free, room-temperature conditions of the team’s new carbon insertion strategy make it a compelling candidate for use in DEL platforms.

By enabling precise skeletal editing in collaboration with the Damian Young group at the Baylor College of Medicine, Sharma’s approach could significantly enhance the chemical diversity and biological relevance of DEL libraries. This is particularly important as these are two key bottlenecks in drug discovery.

The cost of many drugs depends on the number of steps involved in making them. Adding a carbon atom in the late stages of development can make new drugs cheaper, akin to renovating a building rather than building it from scratch. By making these drugs easier to produce at large scale, we could reduce the cost of healthcare for populations around the world.

In conclusion, Sharma’s team has pioneered a groundbreaking method that accelerates drug discovery and reduces pharmaceutical development costs. Their innovative approach has far-reaching implications for the field of medicine, making it faster, safer, and more cost-effective.