Once Andrei Tokmakoff gets his new laser laboratory operational later this year, he will use the world’s shortest infrared light pulses to pluck molecular bonds like a stringed musical instrument.

Tokmakoff, the Henry G. Gale Distinguished Service Professor of Chemistry, arrived at the University of Chicago in January to tackle new problems in biology with the aid of ultrafast vibrational spectroscopy methods that he has developed.

“He does very sophisticated spectroscopy, in particular vibrational spectroscopy,” said Richard Jordan, professor and chairman of chemistry. “He has developed advanced, laser-based methods that can probe how the bonds in molecules stretch and bend.”

Tokmakoff’s hire is a major component of the chemistry department’s effort to expand from its current 22 faculty members to 27 or 28 within the next two years. “We have targeted three or four important areas to build in. One of them is biological chemistry, those aspects of chemistry that deal with biological problems,” Jordan said.

Tokmakoff does both physical and biophysical chemistry. Physical chemistry — studying the behavior of materials and chemical reactions at the atomic and molecular level — has a long tradition of excellence at UChicago. Biophysical chemistry has emerged more recently as a major campus initiative that encompasses the James Franck Institute and the Institute for Biophysical Dynamics (Tokmakoff is a member of both) and the Biophysical Sciences Program.

A special liquid

Tokmakoff seeks to understand the special behavior of liquid water, protein-water interactions, and the dynamics of protein folding and binding. This includes how hydrogen bonds connect different molecules to one another and how these bonds rearrange themselves so that the liquid flows.

“These are not phenomena that can be described simply in terms of the motion of one molecule,” said Tokmakoff, formerly of the Massachusetts Institute of Technology. “Many of the reasons why it’s so vital to life processes also originate not just as one individual molecule, but how they all collectively interact with biological molecules.”

Andrei Tokmakoff joined the University of Chicago faculty in January as the Henry G. Gale Distinguished Service Professor in Chemistry. His research group conducts experiments that use ultrashort pulses of infrared radiation to visualize molecular biophysical phenomena that constantly move, change and evolve. Photo credit: Robert Kozloff

Tokmakoff generates light bursts at 40-femtosecond intervals with ultrafast vibrational spectroscopy. “Light travels the diameter of a cell or a small pollen grain in that time,” he said. Molecules barely move in 40 femtoseconds (a quadrillionth of a second), which corresponds to the period of a molecular bond vibration.

These ultra-short pulses of infrared radiation “act a bit like stop-motion photography,” Tokmakoff said. Although it’s not real photography, “a sequence of ultra-short bursts of light can capture the motion of an object by freezing it at different points in time. We don’t physically image the molecules, but infrared radiation interacts with the bond vibrations of water,” he said. These interactions reveal the structure of the object in question.

“Through a sequence of these pulses we can design experiments that give us a lot of information about the molecular structure before it changes, even if it is constantly moving,” Tokmakoff explained.

At MIT, Tokmakoff applied ultrafast spectroscopic methods to key problems in chemistry. He discovered that the molecular structure of water evolves in big jumps when the molecules collectively change the connectivity of their hydrogen bonds. “It’s a very strange behavior, but the fact that water does this and does it often really makes it a liquid and allows it to flow.”

“Beyond water we’re also applying the same sorts of methods to a lot of problems in molecular biophysics. Many of the problems that exist there share the characteristics with water that they are messy, complicated, constantly evolving molecular structures,” Tokmakoff said, including protein folding.

Disordered yet functional

Tokmakoff’s group has a special interest in disordered proteins. Molecular biologists primarily conceive of proteins as well-defined, three-dimensional, biologically active structures. “The reason we conceive them that way is because that’s what our experiments tell us,” he said. In fact, many proteins are either partially or fully disordered, yet they can still be functional.

Scientists often talk of proteins connecting like a lock and key, but that analogy falls far short of explaining how two structurally disorganized molecules manage to find and then connect with one another.

Two proteins exhibiting no apparent structure wander around randomly in a cell. When they encounter one another they somehow know that they were made for each other, and they often do this with more efficiency and speed than current theory can explain.

“You’ve got one molecule of thousands and thousands in a cell, and somehow it’s miraculously going to find its one partner and do it so efficiently—it’s just mind-boggling,” Tokmakoff said. Tucked into the many aspects of that problem is the molecular fine print: how a protein recognizes and binds to its partner.

Many classes of proteins exhibit such behavior, and Tokmakoff would like to unlock the secret to that behavior. “We’re in the middle of all kinds of cool experiments,” he said.