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

ABSTRACT: Several mechanisms are known to cause monomeric protein misfolding. Coarse-grained simulations have predicted an additional mechanism exists involving off-pathway, non-covalent 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 these entangled misfolded states are populated in higher-resolution models. However, due to the small size of ubiquitin and λ-repressor, these states are short-lived. In contrast, coarse-grained simulations of a larger protein, IspE, predict it populates long-lived misfolded states. Using an Arrhenius extrapolation applied to all-atom simulations we estimate that indeed these IspE misfolded states have lifetimes similar to the native state, while remaining soluble. We further show these misfolded states are consistent with the structural changes inferred from limited proteolysis and crosslinking 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.

INSTRUMENT(S):

ORGANISM(S): Escherichia Coli

SUBMITTER: Yingzi Xia

LAB HEAD: Stephen D. Fried

PROVIDER: PXD066083 | Pride | 2025-08-11

REPOSITORIES: Pride

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			Action	DRS
	20240708_IspE_U24R1_XL1.mgf	Mgf
	20240708_IspE_U24R1_XL1.raw	Raw
	20240708_IspE_U24R1_XL2.mgf	Mgf
	20240708_IspE_U24R1_XL2.raw	Raw
	20240708_IspE_U24R1_XL3.mgf	Mgf

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

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