PXD066083-1

PXD066083 is an original dataset announced via ProteomeXchange.

Title	Non-native entanglement protein misfolding observed in all-atom simulations and supported by experimental structural ensembles
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-08-11
AnnouncementXML	Submission_2025-08-11_11:01:30.678.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD066083
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Yingzi Xia
SpeciesList	scientific name: Escherichia coli; NCBI TaxID: 562;
ModificationList	carbamoylated residue; deamidated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-13 08:37:50	ID requested
⏵ 1	2025-08-11 11:01:31	announced

10.6019/PXD066083;

10.1126/SCIADV.ADT8974;

submitter keyword: structural mass spectrometry,non-native entanglement

Stephen D. Fried
contact affiliation	Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218, United States. T. C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, United States.
contact email	sdfried@jhu.edu
lab head
Yingzi Xia
contact affiliation	Johns Hopkins University
contact email	yxia39@jhu.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD066083
     1. Label: PRIDE project
     2. Name: Non-native entanglement protein misfolding observed in all-atom simulations and supported by experimental structural ensembles