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Ted Laurence
Video explanation of LLNL protein folding study

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“Probing structural heterogeneities and fluctuations of nucleic acids and denatured proteins”
Proceedings of the National Academy of Sciences, Nov. 14, 2005

LLNL’s Physical Biosciences Institute

“Alternating-Laser Excitation ofSingle Molecules”
Accounts of Chemical Research, Sept. 8, 2005 (PDF)

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November 14, 2005

Protein folding study may lead to better treatment of neurodegenerative diseases

LIVERMORE, Calif. — By learning how and why a protein occasionally folds incorrectly, researchers may be able to better treat victims of Alzheimer’s, mad cow and other neurodegenerative diseases.

Model of the ACBP Protein
A model of the acyl-CoA binding protein (ACBP), one of the proteins studied by Livermore and UCLA researchers.

Working with collaborators from UCLA, Ted Laurence of the Lawrence Livermore National Laboratory’s Physical Biosciences Institute measured varying distances within single protein molecules to understand the process of protein folding.

Using a technique called fluorescence resonance energy transfer or FRET, the team measured distances between two specific points on the protein. Special fluorescent chemical groups – a donor and an acceptor – are attached to those points. If the donor and acceptor are within 8-10 nanometers apart, FRET occurs.

Laurence determined that the approximate fluorescence lifetimes of donors and acceptors in the protein are 3 nanoseconds and 1.5 nanoseconds, respectively.

The lifetime of the donor drops significantly when FRET occurs. “Knowing the lifetime of the molecules within a mixture is especially helpful for protein folding studies,” Laurence said.

In this series of experiments, the group used FRET and ALEX (alternating laser excitation) to probe donors and acceptors on folded and unfolded protein sub-populations. They were able to separate the fluorescence lifetime of the unfolded proteins from the folded proteins.

We got a better understanding of biopolymer structural dynamics, which have a large impact in biology and biosecurity,” Laurence said.

In the study of proteins, researchers have not quite figured out what causes a protein to go from a folded to unfolded state.

But Laurence said the recent study sheds some light on the mystery.

The structure in the energy landscape is what encourages it to fold or not to fold,” he said. “You want to see what protein is doing in an unfolded state and why it folds. Then you can understand why the folding sometimes goes wrong.”

Laurence said protein folding gone awry can provide some keys to as to why certain people are prone to Alzheimer’s or other neurodegenerative diseases. In addition, understanding how and why protein folds can help scientists design proteins to perform specific tasks.

In order to do that, we have to know how to build them first,” he said. “Discovering these risk factor genes is essential for understanding the causes of Alzheimer’s disease and pinpointing targets for drug development and other prevention or treatment strategies.”

The research successfully demonstrates how new optical probe tools can be used to study protein folding and conformational dynamics of biomolecules.

The research appears in the Proceedings of the National Academy of Sciences online edition for the week of Nov. 14-18. It will appear in print in the Nov. 29 edition.

Founded in 1952, Lawrence Livermore National Laboratory has a mission to ensure national security and apply science and technology to the important issues of our time. Lawrence Livermore National Laboratory is managed by the University of California for the U.S. Department of Energy's National Nuclear Security Administration.

Founded in 1952, Lawrence Livermore National Laboratory is a national security laboratory that develops science and engineering technology and provides innovative solutions to our nation's most important challenges. Lawrence Livermore National Laboratory is managed by Lawrence Livermore National Security, LLC for the U.S. Department of Energy's National Nuclear Security Administration.