The Rhythms of Life: Tiny Vibrations Reveal How Proteins Move

Predicting protein structure was, until recently, a difficult and frustratingly slow process. The advent of the prediction algorithm AlphaFold changed everything. Now, scientists can rapidly link a protein’s amino acid sequence to its structure. But proteins aren’t fixed in place; they are dynamic structures that shift between conformations.

Researchers have now found a way to predict these movements with high accuracy and reliability, potentially adding a new dimension to the recent revolution in protein science. Understanding the forces that govern protein motion could help scientists engineer proteins that make these shifts more quickly or efficiently, impacting biological research from drug design to biotechnology. The new paper was published in Science Advances.¹

Visualizing Low-Frequency Protein Vibrations

Shifting protein structures have been difficult to study. Many methods for tracking molecular motion examine small shifts at individually labeled protein sites. Relatively little data exists on bigger, slower movements affecting a protein’s whole structure. To better understand these rhythms, researchers at Arizona State University (ASU) built computer simulations to visualize protein movements called low-frequency vibrations.

“We developed a method to identify these vibrations through natural fluctuations caused by molecular collisions. The natural motions stand out if analyzed with the right tools,” said Matthias Heyden, a study coauthor and molecular biophysicist at ASU, in a statement. “This can be compared to an unlocked door: we can feel quickly if we need to push or pull, while trying to yank the door up and off of its hinges is always hard. The key is that we don’t need to execute the full motion to realize these differences. On a molecular scale, it is even enough to observe tiny fluctuations that are always present at room temperature.”

The team’s molecular dynamics simulation technique is called frequency-selective anharmonic (FRESEAN) analysis. This measures how a protein wiggles as it shifts naturally. By measuring where molecules moved and how quickly they moved during these shifts, FRESEAN can extract data about protein movements which is then fed into new, enhanced movement simulations.

After mapping what these rhythms should look like using FRESEAN, Heyden’s team took five well-studied, but very different proteins, and used their simulation to see if they also swayed to these rhythms. The team studied the five proteins’ energy profiles, which map how easy it is for a protein to adopt a particular shape. The team accurately mapped movements across all five proteins, including one taken from hen eggs and a protease from the human immunodeficiency virus.

Importantly, the researchers could perform these simulations rapidly using FRESEAN. Studying these shape changes used to take weeks or months of computation, but Heyden’s team used powerful graphical processors at ASU to image these shifts in less than a day.

Making More Flexible Proteins

Proteins engineered by humans tend to lack the flexibility and dynamism of their natural counterparts. The team hopes that understanding what makes natural proteins move could help scientists design synthetic proteins with a little more groove, which could perform complex functions that rely on conformational changes.

These shifting simulations could also improve researchers’ understanding of allosteric changes that happen across distant protein regions, leading to new drugs that act on proteins in more targeted and predictable ways.

In short, snooping on these proteins’ hidden dance moves could help scientists develop medicines and molecules that better align with our natural rhythms.