Preventing protein unfolding

February 26, 2016, Northwestern University

When the body loses its ability to fold proteins into the correct shapes, the result can be irreversible and tragic. The accumulation of unfolded or misfolded proteins in the brain causes many devastating neurodegenerative diseases, including Alzheimer's, Parkinson's and amyotrophic lateral sclerosis (ALS).

In order to maintain their functions, structural proteins and engineered, protein-based materials need to avoid unfolding even under large mechanical stresses. Scientists, therefore, are exploring ways to design proteins that can survive extreme mechanical insults.

Northwestern Engineering's Sinan Keten has theoretically demonstrated that small proteins can be reinforced with covalently bonded polymers against mechanical unfolding. His computational model illustrates strategies for using this polymer conjugation to prevent proteins from rapidly unfolding even when stretched or pulled apart.

"If you apply a stress to a protein, we know it will start to unfold," said Keten, assistant professor of mechanical, civil and environmental engineering. "Given that proteins are subject to mechanical forces in the body and in all applications, it will be useful to reinforce them in this way."

Supported by the Office of Naval Research, Keten's research is featured on the cover of the February issue of the journal ACS Nano. Elizabeth DeBenedictis, a PhD student in Keten's lab, and Elham Hamed, a former postdoctoral fellow in Keten's lab, are the paper's first authors. DeBenedictis also created the painting that was used for the journal's cover image.

A protein's shape is related to its function. By coiling and folding into specific three-dimensional shapes, they are able to perform their different biological tasks. Proteins are held together by weak . When they unfold, these bonds break and are often replaced by hydrogen bonds with water.

"Once the water is in there, it's hard to reverse the process," Keten explained. "It's hard for the protein to refold."

Researchers have long known that attaching polymers to proteins can stabilize them thermally. But little is known from a mechanical perspective. Keten's team used a common protein structure, called an alpha helix, and a soft, nontoxic polymer called poly-ethylene-glycol to test the reinforcing strategy under . They found that, through hydrophobic and electrostatic interactions, the polymer can reside near the surface of the protein. This shields its backbone hydrogen bonds from being replaced by bonds with water molecules, enabling the protein to hold its specific shape much longer under constant stress.

"The protein can refold back to its original configuration more easily," he said. "When the polymer is close to the surface, you see refolding."

Not only could this finding inform medicine about how to treat or prevent protein unfolding diseases, but the method could be used to stabilize protein-based biomaterials, which is important giving vaccines longer shelf lives, improving drug delivery and creating stronger scaffolds for tissue engineering.

Next, Keten's team will create a design strategy for determining polymer and interfaces that work well together. The team also collaborates with experimental groups to explore applications that may benefit from Keten's computational models.

Explore further: New computational approach allows researchers to design cellulose nanocomposites with optimal properties

More information: Elizabeth P. DeBenedictis et al. Mechanical Reinforcement of Proteins with Polymer Conjugation, ACS Nano (2016). DOI: 10.1021/acsnano.5b06917

Related Stories

Learning from biology to accelerate discovery

July 6, 2015

A spider's web is one of the most intricate constructions in nature, but its precious silk has more than one use. Silk threads can be used as draglines, guidelines, anchors, pheromonal trails, nest lining, or even food. And ...

Researchers describe the role of water in protein folding

September 21, 2015

A study developed by researchers at the Faculty of Physics of the University of Barcelona (UB), published in the journal Physical Review Letters, describes the contribution of water to the three-dimensional structure of proteins ...

Speed plays crucial role in breaking protein's H-bonds

October 30, 2007

Researchers at MIT studying the architecture of proteins have finally explained why computer models of proteins’ behavior under mechanical duress differ dramatically from experimental observations. This work could have ...

Recommended for you

Fast-moving electrons create current in organic solar cells

January 12, 2018

Researchers at Purdue University have identified the mechanism that allows organic solar cells to create a charge, solving a longstanding puzzle in physics, according to a paper published Friday (Jan. 12) in the journal Science ...

Super-adsorbent MOF captures twice its weight in water

January 11, 2018

Material chemists in the Kingdom of Saudi Arabia have developed a superporous solid made up of a patchwork of metal ions and organic linkers (a metal-organic framework, or MOF) that can suck up to 200% of its own weight in ...

Researchers report first 3-D structure of DHHC enzymes

January 11, 2018

The first three-dimensional structure of DHHC proteins—enzymes involved in many cellular processes, including cancer—explains how they function and may offer a blueprint for designing therapeutic drugs. Researchers have ...

Intoxicatingly light-sensitive

January 11, 2018

ETH chemists have synthesised several variants of THC, the active ingredient in cannabis. Its structure can be altered with light, and the researchers have used this to create a new tool that can be used to more effectively ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

katesisco
not rated yet Feb 27, 2016
So it appears that stress is the major destructor of health by instigating protein unfolding and misfolding in our fragile human form?

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.