PXD055795

PXD055795 is an original dataset announced via ProteomeXchange.

Title	A newly identified class of protein misfolding is observed in all-atom folding simulations and supported by experimental structural ensembles
Description	Several mechanisms intrinsic to a protein’s primary structure are known to cause monomeric protein misfolding. Coarse-grained simulations, in which multiple atoms are represented by a single interaction site, have predicted that a novel mechanism of misfolding exists involving off-pathway, non-covalent lasso entanglements, which are distinct from protein knots and slip knots. These misfolded states can act as long-lived kinetic traps and, intriguingly, may resemble the native state structurally according to those simulations. Here, we examine whether such misfolded states occur in long-timescale, physics-based all-atom simulations of protein folding, focusing on ubiquitin and λ-repressor. Our findings confirm the formation of these entangled misfolded states in this higher-resolution model, some of which share structural similarities with the native state. However, due to the small size of ubiquitin and λ-repressor, these misfolded states are short-lived. In contrast, coarse-grained simulations of a larger, typical size protein, ispE, reveal several long-lived misfolded clusters with non-native entanglements. These misfolded clusters are consistent with digestion patterns observed in Limited Proteolysis and Cross-linking Mass Spectrometry experiments. Using an Arrhenius extrapolation from all-atom simulations we estimate these ispE misfolded clusters can persist for extended periods, potentially months, while remaining soluble. Our results suggest that monomeric proteins can exhibit subpopulations of misfolded, self-entangled states that may explain long-timescale changes in protein structure and function in vivo.
HostingRepository	PRIDE
AnnounceDate	2025-08-11
AnnouncementXML	Submission_2025-08-11_10:56:21.514.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yingzi Xia
SpeciesList	scientific name: Escherichia coli; NCBI TaxID: 562;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-11 20:16:48	ID requested
⏵ 1	2025-08-11 10:56:21	announced

10.1126/SCIADV.ADT8974;

submitter keyword: limited proteolysis,protein folding, all-atom folding simulation

Stephen Fried
contact affiliation	Johns Hopkins University, Department of Chemistry
contact email	sdfried@jhu.edu
lab head
Yingzi Xia
contact affiliation	Johns Hopkins University
contact email	yxia39@jhu.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/08/PXD055795

PRIDE project URI

• PRIDE
  1. PXD055795
     1. Label: PRIDE project
     2. Name: A newly identified class of protein misfolding is observed in all-atom folding simulations and supported by experimental structural ensembles