Non-native entanglement protein misfolding observed in all-atom simulations and supported by experimental structural ensembles Article Swipe

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Protein folding Folding (DSP implementation) Chemistry Repressor Molecular dynamics Native state Atom (system on chip) Biophysics Crystallography Chemical physics Biology Computational chemistry Biochemistry Gene Engineering Computer science Transcription factor Electrical engineering Embedded system

Quyen V. Vu , Ian Sitarik , Yang Jiang , Yingzi Xia , Piyoosh Sharma , Divya Yadav , Hyebin Song , Mai Suan Li , Stephen D. Fried , Edward P. O’Brien ·

YOU? · · 2025 · Open Access · · DOI: https://doi.org/10.1126/sciadv.adt8974 · OA: W4413055455

Several mechanisms are known to cause monomeric protein misfolding. Coarse-grained simulations have predicted an additional mechanism exists involving off-pathway, noncovalent lasso entanglements, which are long-lived kinetic traps and structurally resemble the native state. Here, we examine whether such misfolded states occur in long-timescale, all-atom folding simulations of ubiquitin and λ-repressor. We find that these entangled misfolded states are populated in higher-resolution models. However, because of the small size of ubiquitin and λ-repressor, these states are short-lived. In contrast, coarse-grained simulations of a larger protein, IspE, predict that it populates long-lived misfolded states. Using an Arrhenius extrapolation applied to all-atom simulations, we estimate that these IspE misfolded states have lifetimes similar to the native state while remaining soluble. We further show that these misfolded states are consistent with the structural changes inferred from limited proteolysis and cross-linking mass spectrometry experiments. Our results indicate that misfolded states composed of non-native entanglements can persist for long timescales in both all-atom simulations and experiments.