A research team from Pennsylvania State University has, for the first time, validated the existence of a new type of protein misfolding mechanism at the atomic level through high-resolution computer simulations. This study provides new clues for understanding the association between protein misfolding and diseases such as Alzheimer's and Parkinson's, with the findings published in Science Advances.

Protein misfolding occurs when a protein deviates from its normal path during the formation of its three-dimensional structure, leading to loss of function or toxic accumulation. The misfolding type discovered in this study involves abnormal “entangled states” inside the protein—where amino acid chains form knotted structures when they should not, or fail to entangle when stability requires it. The team confirmed through all-atom simulations that this type of misfolding is more likely to persist in larger proteins and may evade monitoring by the cell's quality control system.

Lead researcher and Chemistry Professor Ed O'Brien stated: “Protein misfolding is the root cause of many diseases and may also accelerate aging. Our simulations are highly consistent with experimental data, laying the foundation for the development of targeted therapies.”

First author Quyen Vu noted that misfolding in small proteins can be quickly repaired, but in normal-sized proteins, the structural complexity makes misfolding more likely to persist long-term. This discovery helps explain the accumulation mechanism of misfolded proteins in cells. O'Brien added: “Clarifying the prevalence and stability characteristics of this type of misfolding will drive research into new therapies for aging and neurodegenerative diseases.”