This switching mechanism is far from simple. “Some proteins interact with one or two other proteins, some with hundreds,” Mintseris explains. Understanding the conditions under which they interact formed the foundation of Mintseris’ practicum experience.
Proteins interact by bonding with one another through a process called docking, often depicted as matching a key with a lock. The reality is more complex.
“Imagine two cubes,” explains Mintseris. “Each has six sides that can bind to any of the six sides of the other cube, so they can bind in 36 distinct ways. Now, what if they were more complex 3D polyhedrons instead of cubes? The number of distinct bonds grows very quickly.”
“Protein structures are far more complex than that. They’re long, knotty, intertwined things made up of several hundred of 20 different types of amino acids. So imagine 200 beads on a string. But before you try to match them up, you squeeze them in your fist to make a globular cluster. Some parts repel, others attract. Somehow, though, they fit together.”
To study docking, Mintseris starts with 3D structural models of proteins known to bind with one another. He then holds one protein stationary and rotates the other. “If you try to match every possible part of the surface to the other surface, the possibilities are so enormous it would take forever.”
Instead, he and others in Weng’s lab use bioinformatic techniques to mine databases for clues about protein docking tendencies. For example, some amino acids like to sit next to one another, and some hydrogen bonding sites have preferential attractions. He distills these insights into mathematical rules, or algorithms, that search for the most likely docking sites. The algorithms greatly reduce the number of puzzle pieces that Mintseris must sort through.
Mintseris learned about the DOE CSGF practicum opportunity from Weng, who introduced him to Eisen at a seminar. “It was easy to tell that he was someone who thinks about a problem in the right way,” Eisen recalls.
“Biology is not orderly,” Eisen continues. “It is the way it is because of evolutionary history. Researchers need the flexibility to listen to what it’s telling us. We’re explorers, not diviners of fundamental truths. It’s rare to find people with math skills who can really do this.”
Eisen’s team probes how and when proteins bond with DNA to switch it on and off. First, though, they have to identify the binding sites. Most researchers search for them by comparing DNA from different species. After mapping out regions known to code for proteins, the regions that both DNA strands have in common are considered the most likely regulatory protein binding sites.