New Science Advances article on non-native entanglement protein misfolding

Our new article, “Non-native entanglement protein misfolding observed in all-atom simulations and supported by experimental structural ensembles,” is out in Science Advances.

This work tests whether a previously predicted mode of protein misfolding, in which a protein forms off-pathway noncovalent lasso entanglements, also appears in higher-resolution all-atom simulations and in experiment. We found that ubiquitin and lambda-repressor can transiently populate non-native entangled states during all-atom folding simulations, showing that this topology-based misfolding mechanism is not only a coarse-grained modeling artifact.

For the larger E. coli protein IspE, the story becomes more persistent. By combining coarse-grained folding simulations, backmapped all-atom simulations, Arrhenius lifetime estimates, limited proteolysis mass spectrometry, and cross-linking mass spectrometry, we identified soluble misfolded structural ensembles that can last on timescales comparable to the native state. Nearly 90% of the experimental structural signals are explained by the simulated misfolded ensembles, supporting the idea that non-native entanglement can create long-lived, near-native kinetic traps.

Interactive visualizations of the IspE structures are available here.