Proteins can go through odd changes as they shift from one stable shape to a different, folded one. [Oregon State University]
Proteins can go through odd changes as they shift from one stable shape to a different, folded one. [Oregon State University]

When proteins undergo folding, they move from one relatively stable conformation to another with extraordinary speed, so quickly, in fact, that the awkward intermediate conformations have always been thought to be beyond direct observation. Yet it turns out that these fleeting in-between states have been preserved in images of native proteins. And these images have been accumulating over the years, in the Protein Data Bank and other repositories, rather like snapshots of poorly posed family members in old photo albums.

At Oregon State University, professor of biochemistry and biophysics Andrew Karplus, Ph.D., and doctoral student Andrew Brereton discovered that the stable shapes adopted by a few proteins actually contained some parts that were trapped in the act of changing shape.

“Actual evidence of these transitions was hiding in plain sight all this time,” said Brereton, lead author on this study. “We just didn't know what to look for, and didn't understand how significant it was.”

“We discovered that some proteins were holding single building blocks in shapes that were supposed to be impossible to find in a stable form,” added Dr. Karplus. “Apparently about one building block out of every 6,000 gets trapped in a highly unlikely shape that is like a single frame in a movie.”

“The set of these trapped residues taken together have basically allowed us to make a movie that shows how these special protein shape changes occur,” Dr. Karplus continued. “And what this movie shows has real differences from what the computer simulations had predicted.”

These findings appeared October 16 in the journal Science Advances, in an article entitled, “Native proteins trap high-energy transit conformations.” The article focused on a particular kind of transition, the movement of a non-glycine residue between the left side of a Ramachandran plot (that is, phi < 0°) and the right side (that is, phi > 0°). Essentially, such plots indicate which molecular conformations and transitions are more or less energetically favored.

“We report that high-energy conformations with phi ~ 0°, normally expected to occur only as fleeting transition states, are stably trapped in certain highly resolved native protein structures and that an analysis of these residues provides a detailed, experimentally derived map of the bond angle distortions taking place along the transition path,” wrote the authors. “This unanticipated information lays to rest any uncertainty about whether such transitions are possible and how they occur, and in doing so lays a firm foundation for theoretical studies to better understand the transitions between basins that have been little studied but are integrally involved in protein folding and function.”

“In the 1870s, an English photographer named Eadweard Muybridge made some famous photographs that settled a debate which had been going on for decades, about whether horses as they run actually lift all four feet off the ground at the same time,” Dr. Karplus noted. “His novel series of stop-action photos proved that they did, and opened up a whole new understanding of animal locomotion. In a similar way, our results change the way researchers can now look at one of the ways proteins change shape, and that's a pretty fundamental part of life.”

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