Wolynes used this fundamental law to conceptualize folding in a new way. The top of his folding funnel represents all of the possible ways a protein can fold. As individual stages of the protein come together, the number of possibilities decreases and the funnel narrows and eventually reaches its functional native state.
A funnel's rugged landscape is different for every protein. It shows smooth slopes as well as outcroppings where parts of a protein may pause while others catch up, and also traps that could cause a protein to misfold.
"The funnel shows that the protein tries things that are mostly positive rather than wasting time with dead ends," Wolynes said. "That turns out to resolve what was called Levinthal's paradox." The paradox said even a relatively short protein of 100 acids, or residues, that tries to fold in every possible way would take longer than the age of the universe to complete the process.
That may be true for random sequences, but clearly not for evolved proteins, or we wouldn't be here. "A random sequence would go down a wrong path and have to undo it, go down another wrong path, and have to undo it," said Wolynes, who in his original paper compared the process to a drunken golfer wandering aimlessly around a golf course. "There would be no overall guidance to the right solution."
So the funnel is a useful map of how functional proteins reach their destinations. "The only way to explain the funnel's existence is to say that sequences are not random, b
|Contact: David Ruth|