Penn Medicine News Blog: Archives

November 15, 2013 // By Karen Kreeger // Comments

Renaissance Biochemist

Basic Science // Experts // Research // Translational Research Share this article

Dutton head shot sketch Nov 13Les Dutton, Ph.D., will be awarded the 2013 John Scott Award next week. He will be honored with a medal, certificate, and $12,000 for his "work on the elementary processes of oxidation-reduction and the diverse biological events coupled to it." Dutton is the Eldridge Reeves Johnson Professor of Biochemistry and Biophysics, the director of the Johnson Foundation for Molecular Biophysics, a Fellow of the Royal Society, and former chair of the Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania. And an accomplished artist, but more on that later.

The work for which Dutton is cited for the Scott Award - "the elementary processes of oxidation-reduction and the diverse biological events coupled to it” – is an understatement.

“Bottom line – over the years, we have described how quantum mechanics is translated to basic biology via natural selection,” he says. “Every time we breathe, bringing oxygen into our bodies, we activate electron tunneling, which ultimately makes biochemical energy in the form of the molecule ATP. In a way, to put this fundamental knowledge into stark perspective, when humans die, we ultimately die of power failure.”

To understand just how basic Dutton’s work is, we need to first unpack his nomination citation. Oxidation-reduction, or redox for short,is electron transfer, which happens when an electron moves from one molecule to another. Redox is the dual mechanism of oxidation -- the loss of electrons or an increase in oxidation state by a molecule -- and reduction, the gain of electrons or a decrease in oxidation state. Many biological processes rely on the biochemical energy produced by electron transfer in redox reactions: photosynthesis, respiration, and detoxification.

In the 1960s, as a postdoc with the late, eminent Penn biochemist Britton Chance, and since then, Dutton and colleagues have shown how biological electron transfer makes use of the principles of quantum mechanics. Basically, within and between proteins, electrons don’t hop from redox carrier molecule to molecule; they instead “tunnel” as a wave through the molecular space in the proteins.

In the 1980s, Dutton, with his then graduate students at the time, Chris Moser and Marilyn Gunner, applied the Marcus Theory to electron transfer in the early steps of photosynthesis. (Rudolph A. Marcus from the California Institute of Technology won the 1992 Nobel Prize in Chemistry for his eponymous theory, described in the Nobel press release as “perhaps the simplest chemical elementary process, the transfer of an electron between two molecules.)  

No chemical bonds are broken in such a reaction, but changes take place in the molecular structure of the reacting molecules and nearby molecules. This shape shift enables electrons to move between the molecules. This phenomenon was extremely challenging to determine, and what Gunner actually measured for the first time in a natural protein in her Ph.D. thesis. 

By the end of the 1980s, Dutton and Moser broadened the picture and showed how biological systems select – in a Darwinian sense -- from among quantum mechanical parameters known to be important in electron tunneling, such as how much a molecule is vibrating; the type of medium in which a molecule resides, such as water in the human body; and the “driving force” an electron needs to move from one molecule to another; and the distance between the molecules.

As it turns out, natural selection focuses most predominantly on that distance. The Moser-Dutton rule, as it came to be known from a 1999 Nature paper. It lays the rule out in a simple, elegant equation to calculate the rate of electron tunneling in proteins in different biological systems based on the distance between molecules. It is so simple, Dutton says “that the calculations can be done in one’s head.”

The upshot, he says, is “that nature likes a distance of 14 angstroms or less” (1 millimeter = 10,000, 000 Ångstroms) to maintain working electron transfer rates through chains of redox molecules. And the closer the molecules, the faster the transfer.

“If our electron transfer was switched off, we’d all be dead very quickly,” he says. “It’s basic and ubiquitous. About 25 percent of the world’s enzymes are redox proteins, promoting and controlling reactions driven by electron transfer.”

One of these basic reactions is related to magnetism. Many forms of life -- from microorganisms to animals -- are able to sense the Earth’s magnetic field. Certain microorganisms make use of molecules such as magnetite that sense magnetic fields. Birds make use of something more sophisticated to help navigate migration over thousands of miles.

Dutton currently is working with a protein that is equipped with the coenzyme flavin, which acts as a light-activated redox-driven magnetic sensor. He is part of a European Research Council Advanced Grant led by Peter Hore, a chemist at Oxford University, who for some time has been studying the fundamentals of quantum dynamics in molecules that help birds sense and use magnetic fields.   

The idea of this grant is not only to learn about bird navigation but also to learn how to harness these minute navigation devices for something useful to humans. Dutton’s job in this collaboration is to design and construct a flavin-based protein with the magnetic properties of a molecular-scale compass.

This is only the most recent direction Dutton’s laboratory has explored. He has spent the last two decades building a protein platform for a light- and redox-active proteins of many kinds familiar in nature. A paper that brings all of these concepts to fruition recently appeared in Nature Chemical Biology

“We’re trying to cash in on the idea that in nature, flavin and other redox molecules such as hemes [as in hemoglobin] or quinones -- when wrapped in different proteins -- can do many things,” explains Dutton. “We show that one protein platform, with a few chemical tweaks here and there, will incorporate many different redox-active molecules. That platform is a basis from which to create many types of electron-transferring enzymes known in nature -- but our platform is man-made.”  

Strong hints that this may be possible were revealed in 2009 by Dutton, Moser, and their team when a forerunner of this platform was transformed into an oxygen transporter even though its protein structure was unrelated to the iconic structure familiar in the body’s oxygen carriers myoglobin and hemoglobin.

To build their protein, the team started with three amino acids, which code for a helix-shaped column. From this structure, they assembled a four-column bundle with a loop that resembles a simple candelabra. They added histidine amino acids to bind the chemically active heme group that contains an iron atom to be able to bind oxygen molecules. They then added another amino acid called glutamate to provide strain to the candelabra to help the columns open up to capture the oxygen molecule. Since heme and oxygen degrade in water, the researchers also designed the exteriors of the columns to repel water to protect the oxygen payload inside. The recent Nature Chemical Biology paper shows how to make the “candelabra” do other things with the captured oxygen.

“That exercise was like making a bus,” says Dutton. “First you need an engine and we’ve produced an engine. Now we can add other things on to it. Using the bound oxygen to do chemistry was like adding the wheels.”

If you take a look at Dutton’s other pursuits – namely his art, it makes sense that he calls the proteins he builds maquettes, a term borrowed from the fine arts and design worlds. Maquette is French for scale model, used to visualize and test ideas without the cost and effort of producing a full-scale piece.

Dutton maintains a residence and studio in the south of France, the culmination of a painting life that has been active since he was a teen. Over the years he has had exhibitions and at one time even sold a painting of a Liverpool street scene to Lord Snowden, the famed photographer and husband of Princess Margaret. In recent years he has moved to the sale of commissioned pieces that range from riffs on The Last Supper and works by Leonardo DaVinci and Degas to many landscapes that are very much his own. And, with his famed sketched silhouettes of Biochemistry and Biophysics department faculty, he has brought his seemingly disparate worlds together.

blog comments powered by Disqus

Subscribe to Penn Medicine News Blog by Email

Search

Categories

Authors

About This Blog