Seeing the Invisible

800-MHz-NMR800-MHz-NMR spectrometer

We think we know what a protein molecule looks like. Powerful molecular “cameras” give us snapshots of these chains of amino acids, intricately folded into unique shapes. Researchers then use these details to search for potential “targets” where a drug could attach itself and interrupt the function of a disease-causing protein.

But what if these images we rely on are not as accurate as we believe? What if — in the same way a stiff school photo fails to capture the essence of a feisty child — our snapshots only give a simplified and incomplete version of what are in fact complex, flexible and dynamic structures?

It’s this complexity that U of T Biochemistry, Chemistry and Molecular Genetics Professor Lewis Kay is determined to clarify.

Molecules will often twist and turn before settling into a stable form. Kay is charting what exactly they’re doing when in these more unstable, high-energy states. Using nuclear magnetic resonance (NMR) spectroscopy — a technique that measures chemical shifts and gives details of the structure of molecules, even when they don’t produce any observable signs — he is able to “see” the invisible.
This work is shedding light on diseases that have long puzzled researchers. One of the proteins Kay is investi­gating, for example, pairs up with a partner protein to create an enzyme tied to the devastating neuro­degenerative disease amyotrophic lateral sclerosis (ALS).

Close to 20 per cent of ALS patients with an inherited form of the disease have mutations in this enzyme. Typically known to be strong and stable, the proteins involved can misfold and clump together when in an immature form — which is possibly what leads to ALS.

Researchers knew little about what was happening, until Kay’s team was able to follow these flailing proteins and build 3D models of their various unstable states. They managed to pinpoint specific regions where this bizarre behaviour was occurring — regions that could provide new targets for drugs.

If we could stop the misfolding, we could potentially block a chain of biological events leading to ALS. By “seeing” these unseeable molecules, we gain a clearer vision of exactly what we should be aiming for.