Utilizing simulations and experimental data, my lab predicted the existence of a previously undiscovered, widespread class of protein misfolding that can result in soluble, loss-of-function states, some of which evade the proteostasis network. This class of misfolding involves structural changes in geometric motifs called non-covalent lasso entanglements, which are found in 70% of the native structures of globular proteins. In this talk, I will synthesize six lines of evidence: (1) proteome-wide and atomistic simulations establish the prevalence and physical plausibility of self-entanglement misfolding; (2) translation-speed changes from synonymous mutations re-partition folding trajectories into slowly interconverting, near-native entangled ensembles with reduced catalytic efficiency; (3) distributions of entangled microstates rationalize stretched-exponential refolding kinetics; (4) native-like surfaces coupled to these topological barriers explain how some misfolded states bypass chaperones; and (5) limited proteolysis and cross-linking mass spectrometry provide proteome-scale signals of these states in E. coli. Finally, I will present unpublished results showing that these misfolded states are associated with increased nascent protein degradation through the ubiquitin-proteasome pathway in human cells, with structural changes in proteins that occur during yeast mother cell aging, and with a higher likelihood of harboring pathogenic mutations in human disease. Taken together, simulations and experiments are converging on a unified picture in which entanglement misfolding is common, biologically consequential, and measurable.

1. Under review (2025) “A widespread protein misfolding mechanism is differentially rescued by chaperones based on gene essentiality”
2. Sci. Adv. (2025) “Non-native entanglement protein misfolding observed in all-atom simulations and supported by experimental structural ensembles”
3. Sci. Adv. (2025) “Protein misfolding involving entanglements provides a structural explanation for the origin of stretched-exponential refolding kinetics”
4. Nat. Chem. (2023) “How synonymous mutations alter enzyme structure and function over long timescales”
5. Nat. Commun. (2023) “How soluble misfolded proteins bypass chaperones at the molecular level”
6. Nat. Commun. (2022) “Universal protein misfolding intermediates can bypass the proteostasis network and remain soluble and less functional”