Mankind triumphed in a recent “competition” against nature when scientists succeeded in creating a new type of enzyme which brings about a reaction that no naturally occurring enzyme has done. This achievement opens the door to a variety of potential applications in medicine and industry, such as neutralizing poisons and developing medicines.
Enzymes are, without a doubt, a valuable model for understanding the intricate works of nature. These molecular machines –without which life would not exist – are responsible for initiating chemical reactions within the body. In order to create artificial enzymes, a comprehensive understanding of the structure of natural enzymes, their mode of action, as well as advanced protein engineering techniques is needed.
A team of scientists from the University of Washington, Seattle, and the Weizmann Institute of Science, Israel, made a crucial breakthrough toward this endeavor. Their findings were recently published in the scientific journal Nature.
Enzymes are biological catalysts that are made from a string of amino acids, which fold into specific three-dimensional protein structures. The scientists’ aim was to create an enzyme for a specific chemical reaction for which no enzymes currently exist, but which would be beneficial in helping to speed up the reaction. During the first heat of the “competition,” the research team designed the “heart” of the enzymatic machine – the active site – where the chemical reactions take place.
The second heat of the competition was to design the backbone of the enzyme, i.e., to determine the sequence of the 200 amino acids that make up the structure of the protein. Prof. David Baker of the University of Washington, Seattle, used novel computational methodologies to scan tens of thousands of sequence possibilities, identifying about 60 computationally-designed enzymes that had the potential to carry out the intended activity. From the 60 sequences tested, Prof. Baker narrowed the possibilities down to 3 sequences, which proved to be the most active. Drs. Orly Dym and Shira Albeck of the Weizmann Institute’s Structural Biology Department solved the structure of one of the final contestants, and confirmed that the enzymes created were almost identical to the predicted computational design.
But the efficiency of the new enzymes could not compare to that of naturally-occurring enzymes. This is where “mankind” was on the verge of losing the competition to nature, until Prof. Dan Tawfik and research student Olga Khersonsky of the Weizmann Institute’s Biological Chemistry Department stepped in, whereby they developed a method allowing the synthetic enzymes to undergo “evolution in a test tube” that mimics natural evolution. Through rounds of mutation and screening, they were able to improve the enzymes’ efficiency 200-fold compared with the efficiency of the computer-designed template, resulting in a million-fold increase in reaction rates compared with those that take place in the absence of an enzyme.
“Reproducing the breathtaking performances of natural enzymes is a daunting task, but the combination of computational design and molecular in vitro evolution opens up new horizons in the creation of synthetic enzymes,” says Tawfik. “Thanks to this research, we have gained a better understanding of the structure of enzymes as well as their mode of action. This, in turn, will allow us to design and create enzymes that nature itself had not ‘thought’ of, which could be used in various processes, such as neutralizing poisons, developing medicines, as well as for many further potential applications.”