ArticleProceedings of the National Academy of Sciences of the United States of America2016
Microscopic interpretation of folding ϕ-values using the transition path ensemble.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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23 citing papers in PubMed, 58 citations in OpenAlex.
- DRUMBEAT temporally resolved interpretable machine learning model for characterizing state transitions in protein dynamics.Communications biology · 2026Article
- Pathway regulation mechanism by cotranslational protein folding.Communications chemistry · 2025Article
- Recent Advances in Protein Folding Pathway Prediction through Computational Methods.Current medicinal chemistry · 2024Review
- Intrinsically disordered proteins: Ensembles at the limits of Anfinsen's dogma.Biophysics reviews · 2022Review
- Predicting and Simulating Mutational Effects on Protein Folding Kinetics.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Estimating transition path times and shapes from single-molecule photon trajectories: A simulation analysis.The Journal of chemical physics · 2021Article
- Disordered proteins follow diverse transition paths as they fold and bind to a partner.Science (New York, N.Y.) · 2020Article
- Atomistic mechanism of transmembrane helix association.PLoS computational biology · 2020Article
- Effects of Topology and Sequence in Protein Folding Linked via Conformational Fluctuations.Biophysical journal · 2020Article
- Diverse Folding Pathways of HIV-1 Protease Monomer on a Rugged Energy Landscape.Biophysical journal · 2019Article
- Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis.Chemical reviews · 2019Article
- Mechanism of the electroneutral sodium/proton antiporter PaNhaP from transition-path shooting.Nature communications · 2019Article
- Heterogeneity in the Folding of Villin Headpiece Subdomain HP36.The journal of physical chemistry. B · 2018Article
- Peptide and Protein Structure Prediction with a Simplified Continuum Solvent Model.The journal of physical chemistry. B · 2018Article
- Folding pathway of an Ig domain is conserved on and off the ribosome.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- A small single-domain protein folds through the same pathway on and off the ribosome.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Transition path times of coupled folding and binding reveal the formation of an encounter complex.Nature communications · 2018Article
- Transition Path Times Measured by Single-Molecule Spectroscopy.Journal of molecular biology · 2018Review
- Protein folding transition path times from single molecule FRET.Current opinion in structural biology · 2018Review
- Theory, simulations, and experiments show that proteins fold by multiple pathways.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
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Authors and funding
2 authors at 2 institutions in 2 countries.
Funding
Abstract
All-atom molecular dynamics simulations now allow us to create movies of proteins folding and unfolding. However, it is difficult to assess the accuracy of the folding mechanisms observed because experiments cannot yet directly resolve events occurring along the transition paths between unfolded and folded states. Protein folding ϕ-values provide residue-resolved information about folding mechanisms by comparing the effects of mutations on folding rates and stability, but determining ϕ-values by separately simulating mutant proteins would be computationally demanding and prone to large statistical errors. Here we use transition path theory to develop a method for computing ϕ-values directly from the transition path ensemble, without the need for additional simulations. This path-based approach uses the full transition path information available from equilibrium folding and unfolding trajectories, or from transition path sampling, and does not require identification of folding transition states. Applying our approach to a set of simulations of 10 small proteins by Shaw and coworkers [Lindorff-Larsen K, Piana S, Dror RO, Shaw DE (2011) Science 334(6055):517-520; Piana S, Lindorff-Larsen K, Shaw DE (2011) Biophys J100(9):L47-L49; and Piana S, Lindorff-Larsen K, Shaw DE (2013) Proc Natl Acad Sci USA 110(15):5915-5920], we find good agreement with experiments in most cases where data are available. We can further resolve the contributions to fractional ϕ-values coming from partial contact formation versus transition path heterogeneity. Although in some cases, there is substantial heterogeneity of folding mechanism, in others, such as Ubiquitin, the mechanism is strongly conserved.
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