Ed O’Brien, professor of chemistry at Penn State’s Eberly College of Science, is leading a team of researchers that’s taken important steps toward understanding the complex problem of protein misfolding. They do this through cutting-edge atomic-level simulations. O’Brien, who is a co-hire at the Institute for Computational and Data Sciences at Penn State, emphasizes that this research sheds light on critical mechanisms behind protein misfolding, which can lead to various diseases, including Alzheimer’s and Parkinson’s.
The study focuses on how proteins, which are essential for numerous biological functions, can misfold due to errors in their amino acid sequences. When misfolding does happen, proteins can cause severe health problems. Proteins can only work if they fold into precise three-dimensional shapes, or native state.
Understanding the Basics of Protein Folding
Protein molecules are long chains of amino acids folded into complex shapes. Their functionality is largely a function of the specific sequence of those amino acids. This amino acid sequence determines how the protein folds into a three-dimensional structure. Under normal conditions, cells are equipped with quality control machinery that repair or destroy the majority of these aberrant proteins almost instantaneously. O’Brien notes that the majority of misfolded proteins are efficiently corrected or autocatalytically degraded within the cell. Behind that shortcoming lies a more complex issue at play.
The study pinpoints two significant issues linked to protein misfolding. First, some misfolds necessitate retracing steps and unwinding multiple moves to fix their tangled configurations. These misfolds can burrow deep inside the protein’s structural core. This hides them from the cell’s quality control systems.
“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,” – Ed O’Brien
Advancements in Simulation Techniques
The research team ran the largest-scale simulations of this type using all-atom models of two small proteins. This is a major step forward compared to past research which was based on much coarser-grained simulations. Quyen Vu, a member of the research team, clarified why previous approaches fell short. They realized that for these studies they had only been modeling proteins at the amino acid level, frequently missing key details regarding atomic interactions.
“In our previous study, we used a coarser-grained simulation that only modeled the protein at the amino acid level, not the atomic level,” – Quyen Vu
Vu noted that many scientists were skeptical that these highly simplified models could somehow be realistic. The chemical properties and bonding of atoms play a very important role in the folding process. As such, higher-resolution simulations were needed to capture this class of entangled misfolding in full detail.
“But there was concern in the community that such a model might not be realistic enough, as the chemical properties and bonding of the atoms that make up amino acids influence the folding process. So, we wanted to make sure we still saw this class of entanglement misfolding with higher-resolution simulations,” – Quyen Vu
Implications for Health and Disease
Unraveling the mysteries of protein misfolding is more than an ivory tower pursuit. It’s deeply rooted in the fabric of our health and diseases. Ed O’Brien emphasizes that “protein misfolding can cause disease, including Alzheimer’s and Parkinson’s, and is thought to be one of the many factors that influence aging.”
That discovery was a very important step in understanding, and ultimately documenting, the mechanism of protein misfolding. O’Brien elaborates on the potential for translating these fundamental discoveries into therapeutic targets:
“This research represents another step forward in our attempt to document and understand the mechanisms of protein misfolding. Our aim is to translate these fundamental discoveries into therapeutic targets that could help mitigate the impacts of these disorders and even aging,” – Ed O’Brien
O’Brien is optimistic about what this research could unveil for future treatments:
“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,” – Ed O’Brien.