Enhanced fluorescence technique illuminates rapid, coordinated protein folding

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A team of US researchers has gained new insights into how large protein molecules consistently fold themselves into useful shapes. Using a new approach to fluorescence microscopy, Hoi Sung Chung and colleagues at the National Institute of Diabetes and Digestive and Kidney Diseases have shown that the process likely occurs through the coordinated folding of many different parts of each biomolecule. Their results are published in Physical Review Letters.

The protein-folding problem

Proteins are a vast family of large, complex biomolecules that are essential to all living systems. In their "unfolded" states, they often exist as long, disorderly chains of amino acids—but these soon fold into specific 3D shapes vital for their biological function.

This folding process not only occurs extremely quickly (often in fractions of a millisecond); it is also remarkably reliable. While each amino-acid chain could adopt an enormous number of possible conformations, most of which would not produce a functional protein, proteins almost always fold into the same functional structure. This ultimately suggests that the final shape is largely encoded in the amino-acid sequence itself.

Today, researchers have many unanswered questions about how this sequence guides the molecule rapidly and reliably toward the correct structure, without exhaustively sampling all of these possible configurations. Known as the "protein-folding problem," it remains one of the central challenges in biophysics.

Leveraging fluorescence spectroscopy

To shed new light on the process, Chung's team developed a modified form of fluorescence spectroscopy, in which protein samples are labeled with organic dyes. In the conventional version of the technique, dyes are illuminated with light at wavelengths that are absorbed by specific molecular groups called "fluorophores," which emit light at different wavelengths from the absorbed light.

By measuring the emitted photons, researchers can determine the positions of the dye molecules, and in turn, map the structure of proteins with nanoscale precision. However, because protein folding occurs so quickly, the method becomes unreliable if the fluorescence signal is too weak to build up clear measurements before folding events occur.

To overcome this limitation, the researchers prepared protein molecules in a solution where they continuously switched between folded and unfolded states. After labeling them with dye molecules, the team passed the solution through a nanophotonic waveguide structure.

This structure boosted the intensity of the light emitted by the fluorophores, causing them to release many more photons per microsecond. As a result, the researchers could record detailed signals from the molecules even during extremely rapid folding events.

Coordinated folding

As the team expected, the measurements revealed that the actual folding transition occurs on extremely short timescales—lasting only about 0.7 to 4 microseconds. More surprisingly, the data also suggested that larger proteins appear to pass through this transition more easily than smaller ones.

To explain this observation, Chung's team propose that many parts of larger molecules may begin forming their final structures at the same time. Such coordination would make the overall folding process smoother and help the molecule reach its final configuration more efficiently.

According to the researchers, this behavior could have emerged over many millions of years of evolution, allowing proteins to explore numerous possible folding routes before settling on the most efficient ones.

Written for you by our author Sam Jarman, edited by Sadie Harley, and fact-checked and reviewed by Robert Egan—this article is the result of careful human work. We rely on readers like you to keep independent science journalism alive. If this reporting matters to you, please consider a donation (especially monthly). You'll get an ad-free account as a thank-you.

Publication details

Chi-Jui Feng et al, Cooperative Native Contact Formation Facilitates Free Energy Barrier Crossing in Protein Folding, Physical Review Letters (2026). DOI: 10.1103/2q9m-4scc

Journal information: Physical Review Letters

Key concepts

Evolution, MolecularBiomolecular & subcellular processesConformation & topologyStructural propertiesBiomoleculesNanostructures

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