Protein folding mystery solution: research explains core packing fractions

In organisms, all proteins (a type of biological polymer composed of hundreds of amino acids) remove certain functions such as catalysts, molecular transport, and DNA repair. To perform these functions, you must fold it into a specific shape. This is an important and complicated process in life, and despite advances in this field, many unanswered questions remain about this process.

Research published in PRX Life could shed some light on this issue and lead to new ways to design proteins for drug therapy, new biomaterials, and other applications.

Researchers led by Corey O’Hern developed a computational model for all globular proteins in the online database Protein Data Bank, measuring internal core regions to determine whether they are clustered. The core packing percentage for all proteins was 55%. In other words, 55% of the space was made up of atoms. This led the research team to two questions:

“Why did they all have the same value? And specifically, why is the value 55%?” said O’Hern, a professor of mechanical engineering, materials science, physics and applied physics. “The answer is that when protein becomes jam or rejimmy, the packaging rate increases.”

In other words, the individual amino acids that make up the protein core could not be further compressed when the protein was folded. The packaging rate at which an object jams depends heavily on its shape. For example, a sphere object jams at a packing rate of 64%.

“But amino acids come in complex forms,” ​​O’Hern said.

“Some amino acids are fairly spherical, but most of them extend due to their side chains and are crude due to all of the hydrogen atoms attached.

An interesting future direction is whether the protein core packing fraction is more dense than what is seen for protein under physiological conditions. For example, there has been research on high-pressure proteins, mimicking the pressures of deep ocean hydrothermal, which may possibly be related to the original synthesis of organic molecules.

Structural characterization of proteins at high pressure indicates that the protein core packing fraction can increase to 58-60%. Therefore, this study is also relevant to understanding the origins of life.

“We’ve learned the properties of protein cores under typical folding conditions, so protein core packing may not need to stop at 55%,” said PhD Alex Grigas. He is a candidate for O’Hern’s lab and lead author of the paper.

“Changing the solvent conditions, pressure, or temperature jumps may allow us to pack amino acids more efficiently.”

O’Hern added that protein design is currently focused on creating new sequences of amino acids to design new protein structures and functions.

“Now, this work opens up the possibility that new protein structures and functions can be designed simply by changing folding conditions, even if the same amino acid sequence is present.”