I’ll see your hydrogen and raise you a deuterium*

Have you ever heard of hydrogen exchange as an ana­lyt­ical tech­nique? I hadn’t until the day before yes­terday. Actu­ally, I hadn’t heard of hydrogen exchange, period. Forget the qualifier.

I know you’re bursting at the seams to find out, so I won’t make you wait any longer. Hydrogen exchange is exactly what it claims to be: the exchange of hydrogen atoms.…

Okay. So what does that mean?

John Engen of the depart­ment of chem­istry and the Bar­nett Insti­tute has been working with this tech­nique since his days as a PhD can­di­date and, more recently, has devel­oped an ana­lyt­ical instru­ment that makes uti­lizing the process more approach­able. Here’s how it works:

Pro­teins are big, lum­bering mol­e­cules con­sisting of thou­sands of atoms. They are arranged in a well-​​defined sequence and then folded into what may seem like an amor­phous ball of knotted-​​up yarn but is actu­ally a very spe­cific struc­ture with pockets and helices per­fectly sit­u­ated for the pro­tein to do its job. Hydrogen atoms dec­o­rate pro­teins throughout these intri­cate designs.

In your average Joe pro­tein, hydrogen atoms have one proton and zero neu­trons, giving them an atomic mass of 1. Deu­terium is hydrogen’s black sheep brother, weighing in at 2 atomic mass units with a proton and a neutron.

Since deu­terium and hydrogen are the same ele­ment with a sim­ilar atomic struc­ture, they are inter­change­able. Drown a pro­tein in a bottle of deu­terium oxide (aka heavy water or D2O), and the hydro­gens on the sur­face will be replaced by deu­terium, which is now in much higher supply. Once a pro­tein is cov­ered with deu­terium atoms instead of hydrogen, the mass will increase significantly.

And this, my friend, is where the ana­lyt­ical piece comes in. Say you have a reg­ular pro­tein and a pro­tein from a can­cerous cell and you want to know what is dif­ferent about the two. Sub­merge each in D2O and then weigh them with a “mass spec­trom­eter” (a com­pli­cated mol­e­c­ular scale).

Think back to our knotted-​​up yarn ball. The can­cerous yarn ball might be a little less knotted up, per­haps more stringy with areas that were once hidden inside the con­glom­er­a­tion now exposed. Since the more readily exposed areas of the pro­tein will undergo hydrogen exchange first, a can­cerous pro­tein may weigh more than the reg­ular pro­tein because it had more oppor­tu­ni­ties for deu­terium to hitch a ride.

But Engen’s tech­nique doesn’t just tell you there’s a dif­fer­ence. By chop­ping the pro­tein up into smaller frag­ments and weighing each sep­a­rately, it can tell you specif­i­cally where that dif­fer­ence occurs — exactly what is changed in this messed up cancer protein?

But why would you want to know that in the first place? Well, that’s a whole other blog post, but I’ll give you a hint: if we know how cancer works, we come that much closer to kicking it in the butt.

*I have zero knowl­edge of poker. Please accept my apolo­gies if this title is com­pletely nonsensical.

Photo: Sero­tonin Acetyl­trans­ferase, a pro­tein involved in the con­ver­sion of sero­tonin to melatonin.