In protein folding, internal friction may play a more significant role than previously thought

Apr 24, 2012
This is an amino acid chain folding into a three-dimensional protein. Credit: Benjamin Schuler

An international team of researchers has reported a new understanding of a little-known process that happens in virtually every cell of our bodies.

Protein folding is the process by which not-yet folded chains of assume their specific shapes, hence taking on their specific functions. These functions vary widely: In the human body, proteins fold to become muscles, hormones, enzymes, and various other components.

"This process is still a big mystery," said UC Santa Barbara physicist Everett Lipman, one of several authors of a paper, "Quantifying internal friction in unfolded and intrinsically disordered proteins with single-molecule spectroscopy." The paper was published in the .

A protein's final shape, said Lipman, is primarily determined by the sequence of amino acid components in the unfolded chain. In the process, the components bump up against each other, and when the right configuration is achieved, the chain passes through its "" and snaps into place.

"What we would like to understand eventually is how the chemical sequence of a protein determines what it is going to become and how fast it is going to get there," Lipman said.

This is the microfluidic mount devised to monitor a denatured protein as it folds. Credit: Shawn Pfeil

Using a microfluidic mixing technique pioneered in the UCSB physics department by former graduate student Shawn Pfeil, the research team, including collaborators from the University of Zurich and the University of Texas, was able to monitor extremely rapid reconfiguration of individual as they folded.

In the microfluidic mixer, a "denaturant" chemical used to unravel the proteins was quickly diluted, enabling observation of folding under previously inaccessible natural conditions. The measurements demonstrated that internal friction plays a more significant role in the folding process than could be seen in prior experiments, especially when the protein starts in the more compact unfolded configuration it would have in a denaturant-free living cell.

"At those size scales, everything is dominated by friction," said Lipman, comparing the environment of a protein molecule in water to a in molasses. Friction between the molecule and its liquid environment is an issue, as well as the "dry" friction that is independent of the surrounding solvent.

Internal friction slows down the folding process by reducing the rate at which the amino acid chain explores different configurations that may lead to the transition state. The longer it takes to find its native state –– its final form –– the higher the likelihood it could get stuck in an unfolded state.

"When it is unfolded, it is more vulnerable to being trapped in a misfolded state, or to aggregation with other unfolded protein molecules," said Lipman. Aggregation of misfolded proteins is thought to be a contributor to many types of diseases, such as the amyloid plaques that are associated with Alzheimer's disease. Alternatively, the unfolded and not usable protein could be broken back up into its component amino acids by the cell.

While there is no confirmed link between internal friction and aggregation, or any pattern of friction for one protein that affects others in the same way, Lipman and his colleagues are getting closer to understanding the degree to which internal friction affects the protein folding process.

"These measurements show that under realistic conditions, internal friction plays a significant role in the dynamics of the unfolded state. If a model of the protein folding process doesn't account for this, it will need to be reconsidered," he said.

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HannesAlfven
1 / 5 (1) Apr 25, 2012
The "transition state" is a gel phase transition. This has been extensively covered by Gerald Pollack in Cells, Gels and the Engines of Life. Protein folding is most fundamentally an electromagnetic process, but it is best understood in terms of the behavior of bio-polymers. Looking to mechanical processes - like pumps and channels - to explain biochemical processes is a dead-end approach, because you will never achieve the efficiency required to operate an organism by that route. The most efficient system is one which is quantum coherent, and the only way that Nature could even possibly pull it off is by taking full advantage of water's ability to rapidly switch between structured and unstructured states. The enzymes are what regulate this switching. The alternating charges on the surfaces of enzymes are sized specifically to accept the water molecule.
kevinrtrs
1 / 5 (5) Apr 25, 2012
I haven't read the paper so one can only assume that the researchers were looking at self-folding proteins that don't need/use any chaperones inside the cell. Their use of a de-naturant and observation outside of the cell dictates that assumption. This means that their work has a long way to go to explain how friction applies when chaperones are utilized.
The high energy barriers that are to be overcome in proteins that need chaperones to expedite folding means that this friction theory is headed for some great turbulence in those cases. good luck to them.
TkClick
1 / 5 (1) Apr 25, 2012
Of course the denaturated proteins are affected with internal friction, this is the whole nature of denaturation. In this sense the correct article name should sound "In protein DENATURATION, internal friction may play a more significant role than previously thought". The extrapolation of this conclusion to the protein folding may be misleading.
Origin
not rated yet Apr 25, 2012
The astringent taste of tannin is caused with protein denaturation in saliva. The tannin contains phenolic groups, which dehydrate the proteins in similar way, like the egg white during boiling. We experience a rough tongue feeling after tasting of tannin just because of higher friction between molecules of denaturated proteins in saliva.
HannesAlfven
1 / 5 (3) Apr 25, 2012
By observing the comments here, it appears that biology is in the same exact funk that cosmology is in: People are still refusing to grasp the underlying electrodynamic nature of what they are seeing around them. To think that humans are somehow smarter than Nature, insofar as *we* can create efficient, complex electrodynamic circuits and Nature is stuck with mechanics, is really testament to the power of our own egos.

In cosmology, there is a huge problem with awareness of what a plasma is, and how they tend to behave in the laboratory. That's in spite of the fact that plasma is the universe's preferred state for the matter which we *can* see. This is an unmitigated disaster in that discipline.

In cell biology, it seems, the problem is almost identical in nature, except that it pertains specifically to a lack of awareness of what a gel is, and how they tend to naturally behave. The refusal to listen to the outsiders on this point can stall biology for decades.