Les Dutton turns to proteins for engineering advice.
Energy—and the ability to store, transform and use it—is what keeps life humming along. That’s the big picture. Now take any living organism and zoom in to the molecular level. You’re bound to find that much of the energy that drives your creature comes from a type of chemical reaction known as oxidation-reduction, or redox.
Nature has mastered the art of redox. Les Dutton, Ph.D., is learning at the foot of that master in hopes of designing molecular machines that can help us meet civilization’s growing energy demands.
Dutton is focusing his investigations on the proteins behind redox reactions in living organisms. By deciphering how these proteins control the movement of electrons, he ultimately aims to create artificial proteins that could catalyze redox reactions for applications in energy and medicine.
The Art of Moving Electrons
Oxidation-reduction reactions—in which one molecule, atom or ion loses electrons (oxidation) and another one gains electrons (reduction)—are ubiquitous in nature. These reactions are behind photosynthesis, cellular respiration, chemosynthesis and other key processes that keep living things alive.
The critical step in a redox reaction is the movement of electrons. Over billions of years of natural selection, organisms have evolved a variety of clever electron-transport machines to accomplish this task. Dutton’s work focuses on deciphering how these machines work.
The basic architecture of nature’s electron-transport machines is a set of proteins embedded in a biological membrane. These proteins enable electron transfer across membranes using electrical and pH gradients. The proteins place different types of redox centers—critical areas of the proteins that catalyze redox reactions—close enough together to allow electrons to tunnel from one center to the next in milliseconds. These electron tunnels are the key to how living systems control the speed and direction of electrons, making them fundamental to many biological processes.
“Everything is driven by electron transfer. In biology, in our own systems, every system is rooted, built upon electron transfer.” – Leslie Dutton
Building a Better Protein
Dutton doesn’t just want to watch redox reactions in nature. He wants to get in the driver’s seat by building synthetic proteins that can harness the power of redox reactions to meet societal needs. He calls these man-made proteins “maquettes.”
Dutton has developed a set of engineering guidelines for maquettes based on natural proteins. Starting with a simple artificial protein scaffold, he experiments with introducing functions by progressive, iterative and reversible design steps to construct simple, functioning proteins.
The hope is that these programmable synthetic proteins can ultimately be applied to helping meet energy needs or, in medical and clinical settings, to replace proteins in the human body that are not functioning properly.
In principle, maquettes don’t just mimic nature—they improve upon it. The pressures of natural selection can result in unnecessarily complex systems; designing proteins from scratch could allow the creation of streamlined systems without that extra baggage. “We are making proteins that reproduce the kinds of things that are in nature, but doing it in a very simple structure,” said Dutton.
Dutton acknowledges there’s a long way to go. “All the bioinspired machines that are being developed today—none of them can actually match the biology,” said Dutton. “The efficiency [of natural systems] is five times better than anything made by man.” But that won’t stop him from trying.
Les Dutton is Eldridge Reeves Johnson Professor of Biochemistry and Biophysics at the University of Pennsylvania.