ArticlePLoS computational biology2009
A kinetic model of trp-cage folding from multiple biased molecular dynamics simulations.
Article in PLoS computational biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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86 citing papers in PubMed.
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- Quantifying Unbiased Conformational Ensembles from Biased Simulations Using ShapeGMM.Journal of chemical theory and computation · 2024Article
- Effect of Main and Side Chains on the Folding Mechanism of the Trp-Cage Miniprotein.ACS omega · 2023Article
- The "Beacon" Structural Model of Protein Folding: Application for Trp-Cage in Water.Molecules (Basel, Switzerland) · 2023Article
- Folding-unfolding asymmetry and aRoyal Society open science · 2023Article
- Analysis of Protein Folding Simulation with Moving Root Mean Square Deviation.Journal of chemical information and modeling · 2023Article
- The Role of Transient Intermediate Structures in the Unfolding of the Trp-Cage Fast-Folding Protein: Generating Ensembles from Time-Resolved X-ray Solution Scattering with Genetic Algorithms.The journal of physical chemistry letters · 2023Article
- Topological bio-scaling analysis as a universal measure of protein folding.Royal Society open science · 2022Article
- Differential ion dehydration energetics explains selectivity in the non-canonical lysosomal KeLife · 2022Article
- Integrative structure determination reveals functional global flexibility for an ultra-multimodular arabinanase.Communications biology · 2022Article
- The auto-inhibition mechanism of transcription factor Ets-1 induced by phosphorylation on the intrinsically disordered region.Computational and structural biotechnology journal · 2022Article
- Resolving Dynamics in the Ensemble: Finding Paths through Intermediate States and Disordered Protein Structures.The journal of physical chemistry. B · 2021Article
- Unsupervised Learning Methods for Molecular Simulation Data.Chemical reviews · 2021Article
26 more citing papers are in PubMed but not listed here.
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4 authors.
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Abstract
Trp-cage is a designed 20-residue polypeptide that, in spite of its size, shares several features with larger globular proteins.Although the system has been intensively investigated experimentally and theoretically, its folding mechanism is not yet fully understood. Indeed, some experiments suggest a two-state behavior, while others point to the presence of intermediates. In this work we show that the results of a bias-exchange metadynamics simulation can be used for constructing a detailed thermodynamic and kinetic model of the system. The model, although constructed from a biased simulation, has a quality similar to those extracted from the analysis of long unbiased molecular dynamics trajectories. This is demonstrated by a careful benchmark of the approach on a smaller system, the solvated Ace-Ala3-Nme peptide. For theTrp-cage folding, the model predicts that the relaxation time of 3100 ns observed experimentally is due to the presence of a compact molten globule-like conformation. This state has an occupancy of only 3% at 300 K, but acts as a kinetic trap.Instead, non-compact structures relax to the folded state on the sub-microsecond timescale. The model also predicts the presence of a state at Calpha-RMSD of 4.4 A from the NMR structure in which the Trp strongly interacts with Pro12. This state can explain the abnormal temperature dependence of the Pro12-delta3 and Gly11-alpha3 chemical shifts. The structures of the two most stable misfolded intermediates are in agreement with NMR experiments on the unfolded protein. Our work shows that, using biased molecular dynamics trajectories, it is possible to construct a model describing in detail the Trp-cage folding kinetics and thermodynamics in agreement with experimental data.
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