Protein-folding discovery opens a window on basic life processes

October 16, 2015

Biochemists have discovered “impossible” shapes of proteins as they shift from one stable shape to a different, folded one. (credit: Oregon State University)

Biochemists at Oregon State University have made a fundamental discovery about protein structure that sheds new light on how proteins fold — one of the most basic processes of life. Even the process of thinking involves proteins at the end of one neuron passing a message to different proteins on the next neuron.

The findings, announced today (Oct. 16) in an open-access paper in Science Advances, promises to help scientists better understand some important changes that proteins undergo.

Scientists previously thought is was impossible to characterize these changes, in part because the transitions are so incredibly small and fleeting. Proteins convert from one observable shape to another in less than one trillionth of a second, and in molecules that are less than one millionth of an inch in size. These changes have been simulated by computers, but no one had ever observed how they happen.

Hiding in plain sight

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

X-ray crystallography has been able to capture images of proteins in their more stable shapes. But the changes in shape needed for those transitions are fleeting and involve distortions in the molecules that are extreme and difficult to predict.

What the OSU researchers discovered is that these stable shapes actually contained some parts that were  trapped in the act of changing shape, conceptually similar to finding mosquitos trapped in amber.

“We discovered that some proteins were holding single building blocks in shapes that were supposed to be impossible to find in a stable form,” said Andrew Karplus, the corresponding author on the study and a distinguished professor of biochemistry and biophysics in the OSU College of Science.

“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,” Karplus said. “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. And what this movie shows has real differences from what the computer simulations have predicted.”

As with most fundamental discoveries, the researchers said, the full value of the findings may take years or decades to play out.

The movie below, created by Andrew E. Brereton and P. Andrew Karplus, is an alanine dipeptide animation generated according to the “general” model of the ψ ~ +90° conformational transition described in their paper.

Abstract of Native proteins trap high-energy transit conformations

During protein folding and as part of some conformational changes that regulate protein function, the polypeptide chain must traverse high-energy barriers that separate the commonly adopted low-energy conformations. How distortions in peptide geometry allow these barrier-crossing transitions is a fundamental open question. One such important transition involves the movement of a non-glycine residue between the left side of the Ramachandran plot (that is, ϕ < 0°) and the right side (that is, ϕ > 0°). We report that high-energy conformations with ϕ ~ 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. 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. Also, the context of one such residue shows that even a designed highly stable protein can harbor substantial unfavorable interactions.