Searching for Clues to Biological Functions
Thirumalai Creates Course-Grained Models to Study Protein Folding
For more than two decades, Chemistry Professor David Thirumalai and his research team have studied how biomolecules function. "If you place the simplest cell in a glucose medium, it will double itself every 40 minutes," he explains, citing two of the most important measures of functionality: the length of the cell and the timing of the replication.
"When a cell makes protein, the protein will fold, going from an extended to a more compact shape in milliseconds," describes Thirumalai. "Many, many proteins are synthesized, and they signal each other over time scales ranging from microseconds to minutes."
Discovering how proteins fold and aggregate is critical, according to Thirumalai, " because those aggregated states are all involved in the development of disorders such as Alzheimer's and Parkinson's diseases. We are hopeful we may find a clue to preventing these diseases."
Theories from physics have guided his team's development of coarse-grained models to analyze the folding capacities of DNA, RNA and proteins. Their work was cited this fall in an article in Nature Communications.
"Our research group is primarily focused on discovering general principles that govern the folding of biomolecules using a combination of theoretical and computational strategies," says Thirumalai, whose current team consists of four graduate and eight post-doctorate students. Much of their work focuses on folding mechanisms of large protein and RNA molecules; causes of misfolding in proteins; and variations in the folding mechanisms of proteins in response to changes in environment.
In creating course-grained models, Thirumalai notes, "You don't need to know what every atom is doing with every molecule, but you need a rough idea." He compares his work to constructing a map of the United States. "You don't want to include every street, but you need a rough idea of where your relatives live." By dividing cells and proteins into manageable pieces, the researchers can demonstrate how the cells and proteins solve problems by folding or segregating and how DNA cells are packaged when the folding occurs.
His team is also interested in systems biology or "what happens when seemingly simple molecules of life conspire together. We are looking at the physics of living systems, using chemical and physical laws to describe how biological systems duplicate and how they fail."
Thirumalai admits that even in those diseases whose molecular origins are somewhat understood, such as sickle cell anemia, a cure still evades scientists. "It is very complicated because molecular action occurs in concert with lots of other activities," he adds. "We want to dissect that molecular action from a theoretical and assimilation perspective. If we can slow down one type of aberrant behavior, it will be a huge achievement."