ArticleProceedings of the National Academy of Sciences of the United States of America2014
Folding pathway of a multidomain protein depends on its topology of domain connectivity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24 citing papers in PubMed.
- Residue-Level Energetic Analysis of Transient Misfolding in the Whirlin PDZ Tandem Reveals a Possible Connection to an AlphaFold-Predicted Alternative Topology.International journal of molecular sciences · 2026Article
- Adjacent domains drive the emergence of misfolded intermediates in the folding pathway of the PDZ4 from MAGI1.BBA advances · 2026Article
- GRB2: A dynamic adaptor protein orchestrating cellular signaling in health and disease.Biochemistry and biophysics reports · 2024Review
- Folding pathway of a discontinuous two-domain protein.Nature communications · 2024Article
- Accurate prediction of protein folding mechanisms by simple structure-based statistical mechanical models.Nature communications · 2023Article
- Different N-Glycosylation Sites Reduce the Activity of Recombinant DSPAα2.Current issues in molecular biology · 2022Article
- The Wako-Saitô-Muñoz-Eaton Model for Predicting Protein Folding and Dynamics.Molecules (Basel, Switzerland) · 2022Review
- Topological bio-scaling analysis as a universal measure of protein folding.Royal Society open science · 2022Article
- Cooperativity and Folding Kinetics in a Multidomain Protein with Interwoven Chain Topology.ACS central science · 2022Article
- Structural and Kinetic Views of Molecular Chaperones in Multidomain Protein Folding.International journal of molecular sciences · 2022Review
- A hierarchy of coupling free energies underlie the thermodynamic and functional architecture of protein structures.Current research in structural biology · 2021Review
- Investigating the trade-off between folding and function in a multidomain Y-family DNA polymerase.eLife · 2020Article
- Hidden kinetic traps in multidomain folding highlight the presence of a misfolded but functionally competent intermediate.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Confinement and Crowding Effects on Folding of a Multidomain Y-Family DNA Polymerase.Journal of chemical theory and computation · 2020Article
- Cotranslational folding allows misfolding-prone proteins to circumvent deep kinetic traps.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Successes and challenges in simulating the folding of large proteins.The Journal of biological chemistry · 2020Review
- Thermodynamics and folding landscapes of large proteins from a statistical mechanical model.Current research in structural biology · 2019Article
- Switching Protein Conformational Substates by Protonation and Mutation.The journal of physical chemistry. B · 2018Article
- Spontaneous refolding of the large multidomain protein malate synthase G proceeds through misfolding traps.The Journal of biological chemistry · 2018Article
- Unified understanding of folding and binding mechanisms of globular and intrinsically disordered proteins.Biophysical reviews · 2018Review
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Abstract
How do the folding mechanisms of multidomain proteins depend on protein topology? We addressed this question by developing an Ising-like structure-based model and applying it for the analysis of free-energy landscapes and folding kinetics of an example protein, Escherichia coli dihydrofolate reductase (DHFR). DHFR has two domains, one comprising discontinuous N- and C-terminal parts and the other comprising a continuous middle part of the chain. The simulated folding pathway of DHFR is a sequential process during which the continuous domain folds first, followed by the discontinuous domain, thereby avoiding the rapid decrease in conformation entropy caused by the association of the N- and C-terminal parts during the early phase of folding. Our simulated results consistently explain the observed experimental data on folding kinetics and predict an off-pathway structural fluctuation at equilibrium. For a circular permutant for which the topological complexity of wild-type DHFR is resolved, the balance between energy and entropy is modulated, resulting in the coexistence of the two folding pathways. This coexistence of pathways should account for the experimentally observed complex folding behavior of the circular permutant.
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