Researchers from the Polish Academy of Sciences, in collaboration with colleagues from Johns Hopkins University and Penn State University, have confirmed a new form of protein misfolding using all-atom computer simulations. This type of misfolding occurs when protein chains form incorrect entanglements — such as loops or lasso-like structures — or fail to form them when needed. These defects can disrupt protein function and persist inside cells by evading quality control mechanisms.

For proper function, proteins must fold into precise three-dimensional shapes. Errors in folding are linked to diseases such as Alzheimer’s and Parkinson’s and are believed to be associated with aging. In earlier research, this class of entanglement misfolding was discovered using coarse-grained simulations that model proteins at the amino acid level. However, there was concern in the scientific community that these lower-resolution models might not capture the full chemical detail of folding, since the atomic interactions that govern amino acid behavior were missing. The new study addressed this issue by using higher-resolution, all-atom simulations and confirmed that entanglement misfolds still occur, demonstrating that the existence of the phenomenon is realistic and biologically relevant.

The researchers found that small proteins could form misfolds (Fig. 1), but these were short-lived and quickly corrected. In contrast, larger proteins showed misfolds that persisted, likely because fixing them would require extensive unfolding and because the defects can be hidden deep inside the protein structure. Simulations of typical-sized proteins confirmed the presence of stable entanglement misfolds.

The team also tracked protein folding experimentally using mass spectrometry. Although the misfolds themselves could not be directly observed, the experiments revealed structural changes in the same regions predicted by the simulations. Entanglement misfolding is particularly concerning because it can be highly stable and remain undetected by the cell’s repair systems. A better understanding of this mechanism may help clarify its role in disease development and aging, and identify potential therapeutic targets.