By Juan Miguel Pedraza
Life is forged in the cellular microcosm of proteins: long, complex, and visually stunning molecules as essential for the amoeba as they are for humans.
That proteins are visually arresting natural works of art is a fact rediscovered recently by UND chemistry doctoral candidate
Neville Forlemu, who's developing software to probe the inner secrets of enzymes at the heart of the body's energy cycle.
In a dexterous display of computer wizardry, Forlemu developed a model that correctly predicted the structure and look of a previously unseen fish enzyme (all enzymes are proteins). This opus, a key part of his research in the computer modeling of enzymes, was featured as the cover illustration of a recent issue of the international journal Biopolymers.
Forlemu, who last fall headed into his fourth year of a five-year Ph.D. program, is doing what the research world calls “computational biophysical chemistry.” That’s scientific shorthand for using mathematics and computer programs to simulate the atomic-level behavior of proteins — especially enzymes — and other substances in the cell. In other words, Forlemu and his colleagues are delving into the connections between physical chemistry — what happens, say, when you join hydrogen to oxygen (you get water) — and the chemical function of biological molecules such as the enzymes in your mouth that help you digest your food.
This gets Forlemu down to the elemental level, looking at relationships between molecules in the cell.
“Using computer models and simulations, we can actually describe some of these interactions fairly accurately,” which is what he did when he used his computer model to create an image of the zebra fish enzyme. “That is basically what I’ve been doing since I got here.”
Ultimately, Forlemu’s computer-based research into the development, structure, and function of enzymes will become part of a pharmaceutical design toolkit. That toolkit will certainly include software specifically designed to “create” new drugs, based on the detailed knowledge of the behavior and function of the biomolecules that keep us alive.
“Drug design is the wave of the future in biochemistry,” said Forlemu. “With increasingly sophisticated computer tools, we will be able to design elaborately targeted pharmaceutical products, perhaps even tailored to individual people.”
Enzymes, he explains, are chemical catalysts that facilitate just about every process in the body, from thinking to digesting food. Enzymes, which mediate about 4,000 biochemical reactions in the body, must function flawlessly; that means every time, all the time. Overproduction, underproduction, or accelerated or tardy production of any one enzyme triggers health problems. A lot of drugs, and also poisons, work by interfering with enzyme function, according to Forlemu.
“Ultimately, my goal is to use the computational models that I’m working with here at UND to design new pharmaceuticals,” said Forlemu, who also has earned a strong documented reputation in the classroom for his lucid explanations of complex chemical processes. Teaching and research go hand in glove for Forlemu. His love of science and of explaining things emerged when he started studying biology in high school in his native Cameroon.
“I enjoyed learning about how the human system carries out its many functions; in particular, I was really fascinated to learn about how enzymes perform their catalysis in the body and also how the nervous system functions,” said Forlemu, who values his teachers as much as he values his own classroom teaching.
Forlemu’s research at UND, under the wing of prolifically published chemist Kathryn Thomasson, has taken him back into the computation and mathematics that he worked on during his undergrad work at the University of Buea in Cameroon.
We’re developing computational methods that are easy to use and reliable to study biological phenomena at the molecular level,” explained Forlemu. Thomasson, who is his Ph.D. advisor, says computational methods and the complex computer models derived from them are essential to “seeing” what is happening at the molecular levels of life processes.
Forlemu’s research resulted last year in a cover story with his name as the lead author in the prestigious peer-reviewed international journal Biopolymers. That same issue featured a cover image of a zebra fish enzyme Forlemu modeled with his computer, creating a never-before-seen picture of that molecule.
“Basically, I’m trying to understand how certain molecules — glycolytic enzymes — affect functions in humans and other organisms at the cellular level,” said Forlemu. Glucose, the sugar that powers every cell in the body, is a convenient fuel for life because it is stable and soluble, so it is easy to transport through the blood, he explained. He’s looking at how glycolytic enzymes — chemicals that help to process sugar — react in the cell with other molecules, such as F-actin, that help the cell maintain its shape and structure.
“I’m trying to elucidate the interactions between glycolytic enzymes and cytoskeletal proteins like F-actin,” said Forlemu. “In a nutshell, I’m trying to answer the following questions: Does the association between these two classes of molecules help in organizing the reactions of the glycolytic pathway? If so, how does this so-called compartmentation occur at a molecular level? Ultimately, I’m investigating whether this leads to, or facilitates, substrate channeling in glycolysis.”
President Kupchella reflects
on research growth at UND
UND has nearly tripled its research and sponsored programs budget since President Charles Kupchella took office in July 1999. He will retire June 30 after nine very productive years. UND Discovery asked President Kupchella to reflect on the research enterprise.
What are some of UND’s research strengths?
We obviously have a number of research strengths here. Among the most significant would be our Energy & Environmental Research Center, which is the largest of our sponsored research, development, and commercialization enterprises. The School of Medicine and Health Sciences has significant programs within it such as neurosciences, cancer research, behavioral and translational research, and it is increasingly moving into other areas, such as the development of vaccines. A third pillar would be the John D. Odegard School of Aerospace Sciences, with its programs in unmanned vehicle systems, atmospheric sciences, and other programs of relevance to the aerospace industry. There are more pockets of strength throughout the University, including engineering (biofuels and engineered surfaces), nursing (behavioral science and nutrition), arts and sciences (such as nanoscience, psychology and ecology), among others. We’re developing additional ones like the areas of life science that will take root in the new Center of Excellence for Life Sciences and Advanced Technologies building.
Can you talk about the value to the research enterprise of the Red River Valley Research Corridor and the Centers for Excellence in Economic Development program?
These two programs have been very important to our success, particularly in terms of new research program development and commercialization. A lot of our run-up in sponsored dollars, for example, comes from a focused interest in key areas of research here at UND for which Sen. Byron Dorgan was able to provide some funding. That has played a big part in our move from $34 million to $100 million dollars in sponsored programs. And it enabled us to build on things that were already research strengths and actually begin to develop some other ones.
Gov. John Hoeven’s Centers for Excellence in Economic Development program has been another great fit. It enabled us to take some things we were doing in Aerospace, like the unmanned aerial vehicles systems program, and make an even stronger center of excellence out of that. It enabled us to build the infrastructure to support entrepreneurship and the Ina Mae Rude Entrepreneur Center, which resulted from a combination of state center of excellence money and private money that came from Ray Rude’s gift to the University. And then, of course, the National Center for Hydrogen Technology at the EERC. These things have all advanced through the combined efforts of the Centers of Excellence program and what Sen. Dorgan has brought to UND through the Red River Valley Research Corridor.