Computer Simulations Reveal How Protein Misfolding Evades Cellular Quality Control

Researchers at Penn State have used atomic-level computer simulations to confirm the existence of a recently identified type of protein misfolding that can disrupt function and persist in cells by avoiding detection. Proteins must correctly fold into precise three-dimensional structures—known as their native state—in order to carry out essential biological roles. Misfolding can lead to loss of function and is associated with diseases such as Alzheimer’s and Parkinson’s, as well as processes linked to aging.

The newly studied misfolding involves changes in the “entanglement” status within a protein’s structure. Entanglement refers to the way segments of the amino acid chain loop around each other, similar to lassos or knots. Problems arise when an entanglement forms where it should not, or fails to form where it should. These alterations can interfere with a protein’s activity and may remain in the cell because they are difficult to reverse and can be hidden from the cell’s quality control mechanisms.

In a prior study, the O’Brien Lab observed this type of misfolding using coarse-grained simulations representing proteins at the amino acid level. Some scientists questioned whether this method was realistic enough, since it does not explicitly model the chemical bonding and atomic details that affect folding. To address this, the research team led by Ed O’Brien carried out higher-resolution all-atom simulations on two small proteins. The results showed that these proteins did form the same type of misfolds as in earlier studies, but the misfolds were short-lived because they were easier to correct.

Quyen Vu, first author of the current study published in Science Advances, explained that in larger proteins, misfolds from previous simulations persisted because fixing them required several steps of unfolding and refolding, and the errors could be buried deep inside the structure, away from quality control systems. Testing this, the team simulated a normal-sized protein at the atomic level and again observed persistent entanglement misfolding.

The team also tracked folding of the proteins used in their simulations experimentally. While they couldn’t directly observe the misfolds in the experiments, structural changes inferred using mass spectrometry occurred in the locations that misfolded in their simulations.

As O’Brien noted, “Most misfolded proteins are quickly fixed or degraded in cells. But this type of entanglement presents two major problems. They are difficult to fix as they can be very stable, and they can fly under the radar of the cell’s quality control systems. Coarse-grain simulations suggest that this type of misfolding is common. Learning more about the mechanism can help us understand its role in aging and disease and hopefully point to new therapeutic targets for drug development.”