Faster by Design, Part 2 of 2

Faster by Design, Part 2 of 2

Scientists Create Enzyme from Scratch

As the business adage goes, “Time is money.” Time is also a valuable resource for living organisms. By themselves, most chemical reactions needed to sustain life occur at too slow a rate under physiological conditions to make life possible. Therefore, out of necessity, life’s chemical reactions are accelerated by special types of biological catalysts called enzymes.

These biomolecules are proteins specifically structured to speed up biochemical activities and operations. Enzymes are capable of increasing the rate of biochemical reactions by over a billion-fold in some cases! If not for enzymes, life would be impossible.

As I mentioned last week, a large team of collaborators recently published papers in Science1 and in Nature2 reporting on two enzymes created from scratch and capable of catalyzing nonbiological chemical transformations.

This work has several important implications: It helps biochemists to develop a better understanding of the relationship between enzyme structure and function. It also establishes an approach to generate novel enzymes which can have a wide array of practical applications. And finally, it affects attempts by life scientists to create artificial life in the lab, and, consequently, impacts the creation/intelligent design/evolution controversy.

Last week I provided the background information to appreciate this work. This week I want to describe the research and discuss its implications.

Though conceptually easy, designing these two enzymes was no trivial undertaking. The strategy employed by the researchers involved:

  • Modeling the reaction mechanism and the transition state of the reaction
  • Determining how to stabilize the transition state by placing chemical groups around the transition state complex
  • Designing an enzyme active site that yields the proper placement of chemical groups in space
  • Constructing the scaffolding of the protein chain to form and accommodate the active site
  • Fine-tuning the resulting enzymes

Executing this strategy required a large team of quantum and computational chemists, protein engineers, biochemists, and molecular biologists to create these biomolecules. The computations needed to design the active site and the initial enzyme architectures required hours and hours of supercomputer time.

It took so much effort to design the active site and protein scaffold primarily because the computational chemists and protein engineers weren’t able to build the enzymes from first principles. Instead they had to piece together the enzymes from the domains of about 100 proteins of known structure. They essentially mixed and matched protein regions, producing mosaic enzymes. Using this approach, they still had to sort through combinations for about 100,000 different protein regions. Once they created a scaffold that appeared to work, they had to optimize it using computational techniques. For one of the enzymes, this process yielded about 58 candidates.

Candidate enzymes were synthesized and evaluated in the lab as catalysts. Of the 58 possibilities only eight performed well enough to take to the next stage.

The structures of the best enzymes were then fine-tuned with in vitro evolution protocols. For one of the created enzymes, the in vitro evolution step improved efficiency by about two hundredfold.

Still, this enzyme operated with an efficiency that was ten thousand to a billion times less effective than enzymes typically found in living systems. According to the authors3:

Although our results demonstrate that novel enzyme activities can be designed from scratch and indicate the catalytic strategies that are most accessible to nascent enzymes, there is still a significant gap between the activities of our designed catalysts and those of naturally occurring enzymes.

Even though the created enzymes fall short of those in nature, this advance truly represents a landmark accomplishment that stands as a towering intellectual achievement in every way. The ability to design enzymes that can catalyze novel, nonbiological chemical reactions will lead to better understanding of protein structure and enzyme catalysis. This methodology will also pave the way for protein engineers to design enzymes with industrial, agricultural, and biomedical utility.

This work also bears on the creation/evolution controversy. At first blush it appears as if scientists are one step closer to creating life in the lab. And if scientists can create life, where does that leave God?

In the face of this concern it’s remarkable to note how much effort it took to design a single enzyme that at best compares poorly with those found in nature. It took a collaborative effort from a large number of some of the finest minds in the world to develop and employ an effective design strategy. These researchers relied on sophisticated mathematical algorithms and technology (supercomputers and laboratory instruments) to carry out their scheme.

If it takes this much work and intellectual input to create a single enzyme from scratch, is it really reasonable to think that undirected evolutionary processes could routinely accomplish this task? And to a superior extent each time an enzyme emerges in nature?

It’s important to keep in mind that the simplest organism requires a few thousand different proteins to exist independently in its environment. How much effort would it take to construct the full range of enzymes needed for life, let alone design them to interact properly with each other? (For more details on life’s minimal complexity see Origins of Life and The Cell’s Design

In addition to the questions it raises about the origin of life, this new research provides direct experimental evidence that life’s molecules (and hence, life) must originate from the work of an intelligent agent, in this case a team of quantum and computational chemists, protein engineers, biochemists, and molecular biologists.

This recognition adds to the powerful case that can be made for intelligent design based on the features of biochemical systems. (See The Cell’s Design)

In light of this research, evolution seems to offer a poor return on investment. I’m investing my time and money behind the case for intelligent design.

Part 1 | Part 2