By listening, scientists learn how a protein folds

By listening, scientists learn how a protein folds

Composer and software developer Carla Scaletti and chemistry professor Martin Gruebele used sound to investigate the dynamics of hydrogen bonds during the folding process of proteins. Credit: Fred Zwicky

By converting their data into sounds, scientists discovered how hydrogen bonds contribute to the lightning-fast rotations that transform a series of amino acids into a functional, folded protein.

Their report, published in the Proceeding of the National Academy of Sciences, provides an unprecedented view of the sequence of hydrogen bonding events that occur when a protein changes from an unfolded to a folded state.

“A protein has to fold properly to become an enzyme or signaling molecule, or whatever its function might be — all the many things that proteins do in our bodies,” says Martin Gruebele, professor of chemistry at the University of Illinois, Urbana-Champaign, who led the new study. composer and software developer Carla Scaletti.

Misfolded proteins contribute to Alzheimer’s disease, Parkinson’s disease, cystic fibrosis and other conditions. To better understand how this process goes wrong, scientists must first determine how a series of amino acids changes shape to its final form in the cell’s aqueous environment. The actual transformations occur very quickly, “somewhere between 70 nanoseconds and two microseconds,” Gruebele said.

Hydrogen bonds are relatively weak attractions that align atoms on different amino acids in the protein. A foldable protein will form a series of hydrogen bonds internally and with the water molecules around it. In doing so, the protein wiggles into numerous potential intermediate conformations, sometimes hitting a dead end and backtracking until it ends up on a different path.






Protein sonication: hairpin in a trap

The researchers wanted to map the temporal sequence of hydrogen bonds that occur as the protein folds. But their visualizations couldn’t capture these complex events.

“There are literally tens of thousands of these interactions with water molecules during the short passage between the unfolded and folded states,” Gruebele said.

So the researchers turned to data sonication, a method of converting their molecular data into sounds so they could “hear” the formation of hydrogen bonds. To achieve this, Scaletti wrote a software program that gave each hydrogen bond a unique pitch. Molecular simulations generated the essential data, showing where and when two atoms were in the right position in space – and close enough together – to form a hydrogen bond.

If the right conditions for binding were present, the software program played a pitch corresponding to that binding. In total, the program sequenced hundreds of thousands of individual hydrogen bonding events.






Using sound to investigate the dynamics of hydrogen bonds during protein folding

Numerous studies suggest that audio is processed about twice as fast as visual data in the human brain, and that people are better able to detect and remember subtle differences in a series of sounds than when the same series is presented visually, Scaletti said.

“In our auditory system, we are very attuned to small differences in frequency,” she said. “We use frequencies and combinations of frequencies to understand speech, for example.”

A protein spends most of its time in a folded state, so the researchers also devised a “rarity” function to identify when the rare, fleeting moments of folding or unfolding occurred.

The resulting sounds gave them insight into the process and revealed how some hydrogen bonds appear to speed up folding, while others appear to slow it down. They characterized these transitions, calling the fastest “highway,” the slowest “meander,” and the intermediate “ambiguous.”

Including the water molecules in the simulations and hydrogen bond analysis was essential to understanding the process, Gruebele said.

“Half of the energy of a protein folding reaction comes from the water and not from the protein,” he said. “Through sonication, we really learned how water molecules settle into the right places on the protein and how they help change the protein conformation so that it is ultimately folded.”

Although hydrogen bonds are not the only factor contributing to protein folding, these bonds often stabilize the transition from one folded state to another, Gruebele said. Other hydrogen bonds can temporarily hinder proper folding. For example, a protein may become stuck in a repeating loop where one or more hydrogen bonds are formed, broken, and reformed – until the protein eventually escapes this dead end and continues its journey toward its most stable folded state.

“Unlike the visualization, which looks like a completely random mess, you actually hear patterns when you listen to this,” Gruebele said. “These are the things that were impossible to visualize, but are easy to hear.”

More information:
Scaletti, Carla et al., Hydrogen bond heterogeneity correlates with protein folding transition state transit time as revealed by data sonication, Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2319094121. doi.org/10.1073/pnas.2319094121

Provided by the University of Illinois at Urbana-Champaign

Quote: By listening, scientists learn how a protein folds (2024, May 20) retrieved May 22, 2024 from https://phys.org/news/2024-05-scientists-protein.html

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