When you’re fighting a ruthless enemy like Alzheimer’s disease, you need to bring everything you’ve got. That’s one of the lessons that undergraduate research assistants are learning in Rajeev Prabhakar’s computational chemistry lab, where College of Arts & Sciences (A&S) researchers are battling Alzheimer’s using the combined weapons of quantum physics, chemistry, biology, computer science and math.
What exactly is computational chemistry? Prabhakar describes it as a fast-emerging branch of chemistry that uses computers to model virtual chemical reactions.
“If you are doing conventional chemistry with test tubes, titrations and mass spectrometers, you might determine that a chemical reaction pathway goes from A to D, but the reaction is so fast that you don’t really understand how it happened,” explains Prabhakar. “What we can do with computers is take the experimental data — points A and D — and use modeling software to identify intermediate phases B and C and everything in between. We can provide the missing pieces of the puzzle.”
This gets to the heart of the challenge with Alzheimer’s disease. Researchers have identified a particular amino acid chain called an amyloid beta peptide that collects in the brains of Alzheimer’s sufferers to form something called a senile plaque. Interestingly, though, the plaque itself isn’t the cause of Alzheimer’s. Researchers have found mice whose brains are riddled with plaque, but don’t have the disease.
“Plaque formation is not the connection,” says Prabhakar. “For patients who suffer from Alzheimer’s, the damage is done much earlier. For plaque to form, you need hundreds of thousands or millions of these amyloid beta peptide bonds. But researchers have found that if only two of these peptides aggregate together, that’s enough to kill neurons and impair memory.”
It would be impossible to use conventional chemistry to analyze the formation of these super-early aggregates composed of two to 10 molecules. The reactions happen way too fast, says Prabhakar.
The solution is to take everything we know about chemical reactions, namely the rules of quantum physics that govern atomic interactions, and plug that into a piece of software. With enough computing power — Prabhakar taps the supercomputing resources at the Center for Computational Science — the software can run the billions of calculations necessary to produce an accurate atomic model of how enzymes in the brain first form these peptides and how they bond together in the earliest stages of the disease.
With a virtual blueprint of the biochemical reaction, Prabhakar and his team can then attack the disease on three different fronts.
“In one scenario, we could design small drug-like inhibitors to block the production of these peptides,” Prabhakar says. “Alternatively, we could create a designer form of an enzyme that degrades or kills amyloid beta peptides already in the brain.”
The third option has to do with the shape of the amyloid beta peptides. Normally the peptides are folded, but they unfold in order to bond with other peptides and form aggregates.
“We could come up with small molecules that stabilize the folded structure,” Prabhakar says. “If they don’t unfold, they won’t aggregate.”
The race to find a cure for Alzheimer’s and other degenerative brain diseases like Parkinson’s and Lou Gehrig’s Disease (ALS) is a global research effort. In Prabhakar’s lab, A&S undergraduates and even Miami-Dade high school students from the SEEDS Program join graduate students in carrying out this important work.
“It’s a very good experience for undergraduates to see how all of these different fields come together — physics, chemistry, computer science, biology and more — and to see the connections between them,” says Prabhakar, whose research assistants have published scientific papers in peer-reviewed journals and gone on to medical school and graduate school.
The other advantage of computational chemistry is that Prabhakar’s students don’t have to sit in the lab all day while their experiments run their course.
“Instead, they can submit their job to the computer and go take their classes,” says Prabhakar. “They can even log in remotely.”
That’s called scientific progress.
Watch a video in which Professor Prabhakar explains the science behind his research or get the basics at The Prabhakar Group site.
