ArticleProceedings of the National Academy of Sciences of the United States of America2019
Generation of the configurational ensemble of an intrinsically disordered protein from unbiased molecular dynamics simulation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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49 citing papers in PubMed, 123 citations in OpenAlex.
- A practical guide to investigating biomolecular condensates: a comment from the plant community.Science China. Life sciences · 2026Review
- Hierarchical multi-timescale structural dynamics of the disordered N-terminal of p53.Nature communications · 2026Article
- Transient tertiary structure in intrinsically disordered proteins revealed by multithermal enhanced sampling.Nature communications · 2026Article
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- pH Sensitivity of the SERF1a Conformational Ensemble.ACS omega · 2026Article
- Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain.Nature communications · 2025Article
- Molecular Dynamics of the Intrinsically Disordered Protein COR15A─A Force Field Validation on Structure and Dynamics.Journal of chemical theory and computation · 2025Article
- The molecular mechanism of temperature-dependent phase separation of heat shock factor 1.Nature chemical biology · 2025Article
- Structure of Full-Length Src Kinase and Its Key Phosphorylated States: Molecular Dynamics Study.International journal of molecular sciences · 2024Article
- Conformational analysis of the IQSEC2 protein by statistical thermodynamics.Current research in structural biology · 2024Article
- Molecular Docking of Intrinsically Disordered Proteins: Challenges and Strategies.Methods in molecular biology (Clifton, N.J.) · 2024Article
- The role of solvation on the conformational landscape of α-synuclein.The Analyst · 2023Article
- Water molecule ordering on the surface of an intrinsically disordered protein.Biophysical journal · 2023Article
- Complex Conformational Space of the RNA Polymerase II C-Terminal Domain upon Phosphorylation.The journal of physical chemistry. B · 2023Article
- Intrinsic disorder and conformational coexistence in auxin coreceptors.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Structural characterization of an intrinsically disordered protein complex using integrated small-angle neutron scattering and computing.Protein science : a publication of the Protein Society · 2023Article
- A synergy between site-specific and transient interactions drives the phase separation of a disordered, low-complexity domain.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Clustering Heterogeneous Conformational Ensembles of Intrinsically Disordered Proteins with t-Distributed Stochastic Neighbor Embedding.Journal of chemical theory and computation · 2023Article
- Generation of unfolded outer membrane protein ensembles defined by hydrodynamic properties.European biophysics journal : EBJ · 2023Article
- Sequence controlled secondary structure is important for the site-selectivity of lanthipeptide cyclization.Chemical science · 2023Article
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Intrinsically disordered proteins (IDPs) are abundant in eukaryotic proteomes, play a major role in cell signaling, and are associated with human diseases. To understand IDP function it is critical to determine their configurational ensemble, i.e., the collection of 3-dimensional structures they adopt, and this remains an immense challenge in structural biology. Attempts to determine this ensemble computationally have been hitherto hampered by the necessity of reweighting molecular dynamics (MD) results or biasing simulation in order to match ensemble-averaged experimental observables, operations that reduce the precision of the generated model because different structural ensembles may yield the same experimental observable. Here, by employing enhanced sampling MD we reproduce the experimental small-angle neutron and X-ray scattering profiles and the NMR chemical shifts of the disordered N terminal (SH4UD) of c-Src kinase without reweighting or constraining the simulations. The unbiased simulation results reveal a weakly funneled and rugged free energy landscape of SH4UD, which gives rise to a heterogeneous ensemble of structures that cannot be described by simple polymer theory. SH4UD adopts transient helices, which are found away from known phosphorylation sites and could play a key role in the stabilization of structural regions necessary for phosphorylation. Our findings indicate that adequately sampled molecular simulations can be performed to provide accurate physical models of flexible biosystems, thus rationalizing their biological function.
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