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Unraveling ProteinsProtein folding has been a major research field for some time, with tens of thousands of published articles in the scientific literature — hundreds this year alone — and numerous well-funded laboratories around the world. Bystroff has found his own niche by seeking out a less-studied problem — unfolding.

However, protein unfolding happens fast.

“Too fast,” says Bystroff. “And once it starts, it doesn’t stop.” It’s extremely cumbersome to analyze using biochemical methods and even then, one only gets a blurry picture.

“Scientists have no clue of what the details are,” says Bystroff. “And that’s my justification for doing it computationally. We have a very detailed look at what’s happening in the computer. And the trick is, to prove to people that what we’re doing in the computer is the same thing that’s happening in the cell.”

Meanwhile, Colón is interested in proteins that misfold. He seeks to understand the fundamentals of protein folding and has zeroed in on the issue of stability.

Most proteins spend most of the time in their folded state, says Colón, but they’re in equilibrium, going back and forth. “During that fraction of a second that they may be unfolded, that’s where they could misfold,” he says. If the misfolded state is more stable than the folded state, then that’s going to be the preferred form — and likely a problem. Thermodynamics are one factor; kinetics (i.e. how fast?) also plays a role. “Is it faster to fold this way or that way?” he asks. Proteins that are prone to misfolding are often trapped in their native state so that they cannot unfold at all during their lifetime in the cell. This property devised by nature is known as kinetic stability.

Mistakes in protein folding are increasingly seen in neurological disorders, like Alzheimer’s and Lou Gehrig’s diseases. Misfit proteins are biological markers for these diseases at the very least, and many researchers are seeking to understand whether they have a causative role as well.

Colón compares a protein to a toddler to illustrate the difference between thermodynamic stability and kinetic stability. “If you have a toddler in a room with lots of toys and the door is open, chances are the toddler is going to stay, even though he may briefly leave the room,” he says. “That’s an example of a thermodynamically stable toddler. He’s there — not because he can’t get out — but because he wants to stay there.”

Put a gate across the door to keep the toddler out of trouble and “then he’s kinetically stable,” Colón says. “It doesn’t matter if he cries and wants to get out. He’s kinetically trapped. Sometimes nature must put a ‘gate’ on proteins, an energy barrier to keep them out of trouble (i.e. misfolding). If one could figure out how nature does this, we may be able to use the same strategy to confer kinetic stability upon proteins.”

The collaboration with Bystroff happened when Colón found a way to identify kinetically stable proteins and needed some way to characterize their common features. Bystroff, with his expertise in computer modeling and his drive to make his models relevant, was the perfect partner.

“It’s a really great situation to have somebody doing experimental work in the same area that we’re doing computational work,” says Bystroff.

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