Simplicity in complexity 

By Dawn Wiseman

Guillaume Lamoureux is studying enzymes at the micro level to gain understanding of cancer’s spread. Magnifying glass

Guillaume Lamoureux is studying enzymes at the micro level to gain understanding of cancer’s spread.

Einstein said, “Everything should be made as simple as possible, but not simpler.” Guillaume Lamoureux (Chemistry and Biochemistry) is using that advice in his research. “When you’re working with proteins made of tens of thousands of atoms, it certainly helps to be able to simplify.”

Lamoureux, a member of Concordia’s Centre for Research on Molecular Modeling (CERMM), is trying to electronically simulate some of the basic processes of life by studying metalloenzymes.

“Enzymes are proteins which enable chemical reactions in the body, everything from respiration to digestion. About one-third to one-half of these enzymes have at least one metal atom, like zinc or magnesium, in their core.”

These few metal atoms appear to be key in making the huge molecules work. “If the metal is taken out, the enzyme does not work.”

There are almost uncountable enzymes in the body. For the moment, Lamoureux is focusing on the ones responsible for tissue growth and remodeling.

“You always hear that we are made of cells,” he said, “but we’re actually made of cells encased in a fibrous matrix.” In tissue growth, enzymes actually break apart this matrix to make room for new cells. Unfortunately, the same enzymes that help heal cuts and burns can be exploited when cells become cancerous.

“Malignant tumours can use these enzymes to degrade surrounding matrix and spread their own growth. This is how cancer metastasizes.” Lamoureux hopes his modelling of the enzyme mechanism will one day help other researchers determine how to stop cancer cells from co-opting this normal and essential bodily process.

“The standard way of revealing these mechanisms is to isolate an enzyme, feed it and see what it does. But that takes a long time,” he explained. “We’re looking to speed up the process with computer simulations.”

Simulations begin with static pictures of known enzymes. “These have been obtained from enzyme crystals which let us see pretty much every atom in the molecule.” He then builds a three-dimensional computer model of the enzyme. What he ends up with is analogous to a mechanical drawing of a machine with thousands of gears. “We know what it looks like, but we don’t yet know how it works.”

Next comes the tricky part. “The rules of quantum mechanics are the truth, but they are complicated,” he smiled. “To apply them to biochemistry, we need to simplify them as much as we can.” The result is a “controlled approximation” of how the enzyme functions in real life. On the computer it appears as a movie.

Each movie is the product of solving millions of large equations which requires supercomputing power. “Five years ago, this work just wouldn’t have been possible. The computer power did not exist.” Now that it does, Lamoureux can develop a simulation in hours or days, not months or years.

The really interesting part comes once the mechanism is simulated. “Then we get to ask ‘what if’ questions.” By knowing how the enzyme works under normal conditions, researchers can change conditions to mimic things like gene defects or the impact of drugs on the enzymes. “We’ll actually be able to see what goes right or wrong in the mechanism.”

Lamoureux’s current work is focused on building a library of known enzyme mechanisms. It is cutting-edge research in the emerging field of functional proteomics. Twenty years from now, he thinks it will be old hat.

“Knowing how computers are getting faster and faster, we’ll almost certainly have a commodity tool in the future. Anyone who knows biology or chemistry will be able to ask these “what if” questions and get an answer they trust almost as much as an experiment. At the very worst, they’ll be able to really focus in on what experiments are worth doing.”


Concordia University