Proteins at the Edge

What do a flock of starlings, solar flares, traffic jams, the event horizon of a black hole, and the human brain have in common?

Each of these systems operates at a critical point, on the boundary dividing order from disorder. Tip the scales one way and you have a chaotic cluster of birds, the other way and you have a stable flock that can’t respond efficiently to its environment. Only at the critical point, at the edge of chaos, can the swarm remain stable and quickly adapt when a predator comes in view. Although these systems are very different, certain aspects of their behavior can be described by distinct mathematical relationships that characterize critical systems.

Studland starlings.
Image Credit: Tanya Hart (CC BY-SA 2.0).

In research published today in the American Physical Society’s Physical Review Letters, a team of researchers have shown that proteins also display critical behavior. This insight could help us better understand the complicated relationship between the structure of a protein and its function, and open the door to valuable new possibilities.

The human body contains many thousands of proteins. They carry out vital functions, ranging from replicating DNA to transporting molecules and breaking down food. Proteins are made from long chains of small molecules known as amino acids. After forming, each protein undergoes a folding process. Its function is determined by the sequence of amino acids and by the three-dimensional shape it forms, called its native state.

Things aren’t exactly cut-and-dry though. Proteins in their native state aren’t rigid, their structures can still fluctuate. For example, a protein might recognize a particular molecule and then change shape upon binding to it. This means that the structure of a protein must be susceptible to, or influenced by, its environment, but also stable enough to maintain its function. This competition between stability and flexibility is a key feature of systems near a critical point.

The idea that biological systems may be on this critical edge is relatively new. Not everyone is convinced, but research continues to support this notion. In the spring of 2015, a group of researchers gathered in Germany for a workshop on critical systems in biology. After attending a few talks, graduate student Qian-Yuan Tang from Nanjing University in China realized that some confusing results from a past protein folding project implied that proteins could be treated as critical systems.

One of the talks that inspired him described research on criticality in the brain, and was given by senior researcher Dante Chialvo from the National University of San Martín and the National Scientific and Technical Research Council in Argentina. On the train ride to the airport after the conference, Tang told Chialvo about his results and convinced him that it was possible to explore the criticality of proteins.

The two began an across-the-globe collaboration, sending graphs and calculations back and forth for over a year. Their goal was to see whether proteins have the same properties as other systems on the edge of a critical point. The study included nearly 5,000 data sets from a databank of protein structures determined by biologists around the world. Each set contained information about the possible structures of a different protein. The structures in each set were similar to one another, but reflected changes in the positions of amino acids.

Tang, Chialvo, and their colleagues analyzed this data, examining how the distance between each amino acid and every other one varies with the different structures for each protein. They extracted the relationships between these distances and variables such as protein size and susceptibility.

This image shows the possible structures (fluctuations) for four different proteins. This research shows that no matter how large a protein molecule is, each amino acid in a protein is correlated to every other one in the same molecule.
Image Credit: Qian-Yuan Tang, Yang-Yang Zhang, Jun Wang, Wei Wang, and Dante R Chialvo.

Their results suggest that the motion of each amino acid is felt by every other one in a protein, enabling the system to process information as quickly as possible. The strength of this relationship increases with the size of the protein, as does the susceptibility of the proteins. They grow in exactly the same way as in biological and physical systems near a critical point. The researchers also found that proteins with larger susceptibility are most frequently observed in nature. Not only do these results imply that the proteins’ native state is critical, but they suggest that evolution may favor protein structures balanced on the edge of stability and flexibility.

What exactly does this mean? Proteins evolved to have functions, says Tang, so understanding the principles that govern their evolution could shed light on how to design useful proteins. Protein design and engineering is an area of research with really exciting potential for treating and preventing diseases, among other applications. The field is growing rapidly, but there are some big challenges—it’s still really tough for scientists to predict how a sequence of amino acids will fold, and to predict exactly what function that fold will produce. Hopefully this work will shed some new light on those important questions.

Now, enjoy this cool video of flocking starlings.

Kendra Redmond

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