Hearing proteins fold

Proteins control everything in the human body, including brain function. Their shape or fold determines their function. When proteins misfold due to amino acid mutations, they can malfunction and cause diseases. Therefore, understanding protein folding is the key to deciphering biological functions but it is very challenging. Using sound, researchers have now visualised how proteins fold (bit.ly/Protein-sonification).

Martin Gruebele and team at the University of Illinois Urbana-Champaign teamed up with musician and software developer Carla Scaletti of Symbolic Sound Corporation, and converted protein-folding data into sound through a process called protein sonification. Proteins fold within a few nanoseconds to microseconds. Researchers visualised how a protein's hydrogen makes bonds with thousands of water molecules within the cell during folding. It is difficult to visualise this three-dimensional event on a 2D computer screen. "One advantage of sound is that you can still hear an event even if it's visually occluded," said Scaletti and Gruebele in an email interview to Shaastra.

To understand the process, Scaletti wrote a software program named Kyma (Greek for wave) that assigned each hydrogen bond a unique pitch. Scaletti took inspiration from computer games, where a metallic sound plays when two swords collide. Applying a similar approach in their simulation, the researchers triggered a specific sound whenever a pair of amino acids were close enough to form a hydrogen bond. "So, we could hear when bonds were forming and we could also distinguish bonds from one another and hear when they formed cooperatively, meaning near-simultaneously," said the researchers.

The team also incorporated an animation combined with a sound that shows the dynamics of molecules. Gruebele named it "The Journey" — the pathway from an initial to a terminal state through intermediate states proceeding at different rates. Some hydrogen bonds speed up folding; some slow down the process. "We could immediately hear that there were patterns of hydrogen bonds associated with unfolded, folded, and transition states — and that these patterns were different between what we called the Highway versus the Meander pathways," the researchers said. She found links between the types of hydrogen bonds, the order in which they formed, and the speed at which the protein transitioned from an unfolded to a folded state, and the results matched experimental data.
 
"Protein folding is crucial for deciphering the mechanisms of diseases related to protein misfolding, such as Alzheimer's and Parkinson's. The methodologies developed in this study could be applied to investigate these diseases at a molecular level," says Soumendranath Bhakat, scientist and the Founder of AlloTec, which develops therapeutics by targeting protein-protein interaction.