Improved Predictions of Phase Behaviour of Intrinsically Disordered Proteins by Tuning the Interaction Range

Tesei, Giulio; Lindorff‐Larsen, Kresten

doi:10.1101/2022.07.09.499434

Cited by 9 publications

(28 citation statements)

References 82 publications

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“…Coarse-grained prior ensemble. We used CALVADOS-2, a recently introduced coarse-grained model optimised to generate structural ensembles of disordered proteins that reproduce well the experimental values of the radius of gyration 38 . We first generated a prior structural ensemble of followed by a back mapping procedure to generate a full atom ensemble (see Methods), which we refer to as the C2 ensemble of Aβ.…”

Section: Alphafold-predicted Structural Ensemble Of Abmentioning

confidence: 99%

“…Coarse-grained model. We calculated the prior ensemble of Αβ and α-synuclein using CALVADOS-2, a coarse grained model for disordered proteins, following the same procedure in the original paper 38 . For Αβ and α-synuclein, we performed five simulations each, at 278 and 298 K, while the simulation time was set to 18 and 35 million steps.…”

Section: Reweightingmentioning

confidence: 99%

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AlphaFold Prediction of Structural Ensembles of Disordered Proteins

Brotzakis

Zhang

Vendruscolo

2023

Preprint

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Deep learning methods of predicting protein structures have reached an accuracy comparable to that of high-resolution experimental methods. It is thus possible to generate accurate models of the native states of hundreds of millions of proteins. An open question, however, concerns whether these advances can be translated to disordered proteins, which should be represented as structural ensembles because of their heterogeneous and dynamical nature. Here we show that the inter-residue distances predicted by AlphaFold for disordered proteins are accurate, and describe how they can be used to construct structural ensembles. These results illustrate the possibility of making structural predictions for disordered proteins using deep learning methods trained on the large structural databases available for folded proteins.

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Section: Alphafold-predicted Structural Ensemble Of Abmentioning

confidence: 99%

Section: Reweightingmentioning

confidence: 99%

AlphaFold Prediction of Structural Ensembles of Disordered Proteins

Brotzakis

Zhang

Vendruscolo

2023

Preprint

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“…We carried out coarse-grained simulations of protein IDRs using the implicit-solvent CALVADOS 2 forcefield (71,106). In CALVADOS, amino-acid residues are mapped to single beads corresponding to their amino-acid type.…”

Section: Idr Modeling and Simulationsmentioning

confidence: 99%

“…Neighboring residues are linked using harmonic bonds with an equilibrium distance of 0.38 nm and force constant of 8033 kJ mol -1 nm -2 . Nonbonded interactions are modeled with a hydropathy amino-acid "stickiness" model using ߣ-parameters from CALVADOS 2 (106). Salt-screened electrostatic interactions are accounted for with a truncated (r c = 4 nm) and shifted Debye-Hückel potential; nonelectrostatic interactions were truncated at 2 nm (106).…”

Section: Idr Modeling and Simulationsmentioning

confidence: 99%

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Insights into the conservation and diversification of the molecular functions of YTHDF proteins

Flores-Tellez

Tankmar

Bülow

et al. 2022

Preprint

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YT521-B homology (YTH) domain proteins act as readers of N6-methyladenosine (m6A), the most common internal covalent modification in eukaryotic mRNA. Members of the YTHDF subclade can determine properties of m6A-containing mRNAs in the cytoplasm of animal and plant cells. Vertebrates encode three YTHDF proteins, and whether they perform specialized or redundant molecular functions is currently debated. In land plants, the YTHDF clade has expanded from just one member in basal lineages to eleven so-called EVOLUTIONARILY CONSERVED C-TERMINAL REGION1-11 (ECT1-11) proteins in Arabidopsis thaliana, named after the conserved YTH domain found at the C-terminus following a long intrinsically disordered region (IDR) at the N-terminus. The origin and implications of YTHDF expansion in higher plants are not known, as it is unclear whether it involves acquisition of fundamentally different properties, in particular of their divergent IDRs. Here, we used the leaf formation defects in ect2/ect3/ect4 mutants to test whether the many Arabidopsis YTHDF proteins can perform the same function if expressed at similar levels in leaf primordia. We show that the ancestral molecular function of the m6A-YTHDF axis in land plants is conserved over YTHDF diversification, and currently present in all major clades of YTHDF proteins in flowering plants. Nevertheless, lineage-specific neo-functionalization of a few members also happened after late duplication events. ECT1, the closest homolog of ECT2/3/4, is one such divergent YTHDF protein. Accordingly, mutation of ECT1 does not aggravate the defective organogenesis of ect2/ect3/ect4 mutants, even though the four proteins are naturally expressed in the same population of primordial cells.

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Combining Experiments and Simulations to Examine the Temperature-Dependent Behavior of a Disordered Protein

Pesce

Lindorff‐Larsen

2023

J. Phys. Chem. B

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Intrinsically disordered proteins are a class of proteins that lack stable folded conformations and instead adopt a range of conformations that determine their biochemical functions. The temperature-dependent behavior of such disordered proteins is complex and can vary depending on the specific protein and environment. Here, we have used molecular dynamics simulations and previously published experimental data to investigate the temperature-dependent behavior of histatin 5, a 24-residuelong polypeptide. We examined the hypothesis that histatin 5 undergoes a loss of polyproline II (PPII) structure with increasing temperature, leading to more compact conformations. We found that the conformational ensembles generated by the simulations generally agree with small-angle X-ray scattering data for histatin 5, but show some discrepancies with the hydrodynamic radius as probed by pulsed-field gradient NMR spectroscopy, and with the secondary structure information derived from circular dichroism. We attempted to reconcile these differences by reweighting the conformational ensembles against the scattering and NMR data. By doing so, we were in part able to capture the temperature-dependent behavior of histatin 5 and to link the observed decrease in hydrodynamic radius with increasing temperature to a loss of PPII structure. We were, however, unable to achieve agreement with both the scattering and NMR data within experimental errors. We discuss different possible reasons for this including inaccuracies in the force field, differences in conditions of the NMR and scattering experiments, and issues related to the calculation of the hydrodynamic radius from conformational ensembles. Our study highlights the importance of integrating multiple types of experimental data when modeling conformational ensembles of disordered proteins and how environmental factors such as the temperature influence them.

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Improved Predictions of Phase Behaviour of Intrinsically Disordered Proteins by Tuning the Interaction Range

Cited by 9 publications

References 82 publications

AlphaFold Prediction of Structural Ensembles of Disordered Proteins

AlphaFold Prediction of Structural Ensembles of Disordered Proteins

Insights into the conservation and diversification of the molecular functions of YTHDF proteins

Combining Experiments and Simulations to Examine the Temperature-Dependent Behavior of a Disordered Protein

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