When a protein folds, a chain of amino acids swings through a myriad of conformations to form a fully folded, functional protein — a rapid and complex process that can be difficult to visualize.
now, Martin GruberA chemist and his team at the University of Illinois at Urbana-Champaign have found a way to use sight and sound to better understand protein folding. He teamed up with a composer and software developer. Carla ScalettiIn a study conducted by Dr. John Myers, co-founder of Symbolic Sound, scientists transformed protein-folding simulation data into a series of sounds of different pitches. Scientists were able to identify patterns in the sounds and infer that the bonds between amino acids play an important role in regulating the folding process. Proceedings of the National Academy of Sciences, It will help scientists unravel the mysteries of protein folding.1
“Sight is one of the most obvious and direct ways we process information, but if you think about it, we often use our ears to pick up cues from our surroundings, and we often don’t realise that we use sound to navigate alongside our sight,” says Golbert.
For their analysis, the team focused on hydrogen bonds – weak bonds that proteins form internally between atoms of amino acids and the surrounding water. These bonds are dynamic, forming and breaking rapidly over time as proteins fold. Because it takes just nanoseconds to microseconds for a protein to transform into its final structure, the scientists had to slow down the process to capture the sounds during their analysis.
“We were a good fit because Martin and his group are interested in mechanics,” Scaletti says, “and we’re interested not only in the spatial structure of proteins, but how that changes over time, and that seemed like a perfect match for sound, because sound doesn’t exist without time.”
Typically, scientists use Molecular dynamics (MD) simulationmodels the physical motion of the folded protein and the water atoms surrounding it.2
“Water is very difficult to visualize,” says Golbert. “When you solve an MD simulation, you see that there is only one protein molecule in the simulation, but there are thousands of water molecules. And it’s hard to see what they’re doing; they just seem to move around randomly. Carla and I wanted to bring order to that chaos.”
The scientists modeled the folding process using the WW domain, a protein domain with two conserved tryptophan residues. They used data from MD simulations of the protein domain folding and unfolding to identify where hydrogen bonds could form. Scaletti then assigned a musical note to each hydrogen bond. When conditions were right for the bond to form, the software played a sound. The notes resulting from a series of bonds that emerged over time gave the scientists an idea of ​​how the protein dynamically changed structure in water.
Scientists could see and hear different patterns of hydrogen bond (H-bond) formation as proteins fold and unfold. A “piano roll” representation of H-bond potential for each folding transition, ordered from shortest duration on the left to longest duration on the right. Time is represented from left to right on the x-axis (multiple transitions are shown side-by-side for comparison). Bond potential is mapped to color and intensity.
Image generated by Carla Scaletti in Kyma
The team captured the noise patterns by listening to the sounds of hydrogen bonds breaking and forming as the protein folds and unfolds. “It’s like listening to a symphony orchestra with many people playing, but with a little effort you can distinguish the individual players,” Golbert said.
The research team combined sonification, visualization, and physics calculations to understand how hydrogen bonds contribute to protein folding and unfolding. Based on the auditory analysis, the team found that proteins follow multiple trajectories as they sprint or saunter toward a folded structure. The team called the slower transitions “snakes,” which appear as if the protein and water interact incorrectly and get caught in a loop of incorrect hydrogen bonds, preventing correct folding before the correct bonds take over the final protein structure. There are also “highways,” where the correct bonds form very quickly and everything falls into place very quickly. Water molecules played a key role in stabilizing proteins and controlling these transitions with their own hydrogen bonds. “We now know why proteins evolved to contain specific amino acids to form the 3D patterns that allow them to fold,” says Goubert.
“This is a great example of using sonification for discovery.” Rosanne Ford“Visually, there’s a lot of things going on in your field of vision at once, like multiple hydrogen bonds in different places in a protein, and your eyes can’t keep track of it all,” said Ford, a chemical engineer at the University of Virginia who was not involved in the work. “But you can hear multiple tones or multiple pitches at once, and that gives you a sense of the changes in hydrogen bonds over time that are hard to see.”
