Biology subjects

Vu, Q. V.

Publications and source records attributed to Vu, Q. V..

4 recordsLinked to original sources

bioRxiv2026

Natively entangled proteins are linked to human disease and pathogenic mutations likely due to a greater misfolding propensity

A recently discovered class of protein misfolding involving native entanglements could be a widespread mechanism by which loss-of-function diseases arise. Here, we test that hypothesis by examining if there is any statistical association between proteins predisposed to misfold in this way and a database of gene-disease relationships. We find that globular proteins containing non-covalent lasso entanglements (NCLEs) in their native structure, which are more prone to misfolding, are 61% more likely to be associated with disease, 68% more likely to harbor pathogenic missense mutations, and their misfolding-prone entangled regions are 64% more likely to harbor pathogenic missense mutations. Protein refolding simulations indicate that these disease associated, natively entangled proteins are 2.5-times more likely to misfold than comparable non-disease proteins that lack native NCLEs. These results indicate that native entanglement misfolding, especially in the presence of missense mutations, have the potential to contribute to a wide variety of diseases. More broadly, these findings open an entirely new space of therapeutic targets in which drugs are designed to avoid these misfolded states and increase the amount of folded, functional protein.

bioinformatics↗

bioRxiv2026

Native entanglement misfolding contributes to age-associated structural changes across the Saccharomyces cerevisiae proteome

Aging at the subcellular level involves the simultaneous decline in the cells ability to maintain protein homeostasis and rise in misfolded proteins through a positive feedback loop. Here, we test if a widespread class of protein misfolding could contribute to proteome aging by examining if statistical associations exist between age-related changes in protein structure, measured by limited proteolysis mass spectrometry data of the aging Saccharomyces cerevisiae proteome, with structural annotations and molecular simulations. We find that globular proteins that are likely to exhibit entanglement misfolding are 121% more likely to exhibit age-related structural changes, and these changes are 59% more likely to be localized to natively entangled regions. Proteins containing native entanglements are seven-fold more likely to misfold, according to simulations, and populate long-lived, near-native misfolded states. Thus, the age-related structural changes in yeast proteins can be explained in part by the accumulation of misfolded proteins involving entanglements.

biochemistry↗

bioRxiv2022

A New Class of Protein Misfolding is Observed in All-atom Folding Simulations

Several mechanisms intrinsic to a proteins 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 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 be long-lived kinetic traps, and in some cases are structurally similar to the native state according to those simulations. Here, we examine whether such misfolded states occur in long-time-scale, physics-based all-atom simulations of protein folding. We find they do indeed form, estimate they can persist for weeks, and some have characteristics similar to the native state. Digestion patterns from Limited Proteolysis Mass Spectrometry are consistent with the presence of changes in entanglement in these proteins. These results indicate monomeric proteins can exhibit subpopulations of misfolded, self-entangled states that can explain long-timescale changes in protein structure and function in vivo. One-Sentence SummaryEntangled misfolded states form in physics-based all-atom simulations of protein folding and have characteristics similar to the native state.

biophysics↗

bioRxiv2021

Ribosome elongation kinetics of consecutively charged residues are coupled to electrostatic force

The speed of protein synthesis can dramatically change when consecutively charged residues are incorporated into an elongating nascent protein by the ribosome. The molecular origins of this class of allosteric coupling remain unknown. We demonstrate, using multi-scale simulations, that positively charged residues generate large forces that pull the P-site amino acid away from the A-site amino acid. Negatively charged residues generate forces of similar magnitude but opposite direction. And that these conformational changes, respectively, raise and lower the transition state barrier height to peptide bond formation, explaining how charged residues mechanochemically alter translation speed. This mechanochemical mechanism is consistent with in vivo ribosome profiling data exhibiting a proportionality between translation speed and the number of charged residues, experimental data characterizing nascent chain conformations, and a previously published cryo-EM structure of a ribosome-nascent chain complex containing consecutive lysines. These results expand the role of mechanochemistry in translation, and provide a framework for interpreting experimental results on translation speed. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/455055v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@14714eeorg.highwire.dtl.DTLVardef@1af3ad7org.highwire.dtl.DTLVardef@1402740org.highwire.dtl.DTLVardef@d11c04_HPS_FORMAT_FIGEXP M_FIG C_FIG For table of contents use only.

biophysics↗