Refinement of α-Synuclein Ensembles Against SAXS Data: Comparison of Force Fields and Methods

Research output: Contribution to journalJournal articlepeer-review

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Refinement of α-Synuclein Ensembles Against SAXS Data : Comparison of Force Fields and Methods. / Ahmed, Mustapha Carab; Skaanning, Line K.; Jussupow, Alexander; Newcombe, Estella A.; Kragelund, Birthe B.; Camilloni, Carlo; Langkilde, Annette E.; Lindorff-Larsen, Kresten.

In: Frontiers in Molecular Biosciences, Vol. 8, 654333, 2021.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Ahmed, MC, Skaanning, LK, Jussupow, A, Newcombe, EA, Kragelund, BB, Camilloni, C, Langkilde, AE & Lindorff-Larsen, K 2021, 'Refinement of α-Synuclein Ensembles Against SAXS Data: Comparison of Force Fields and Methods', Frontiers in Molecular Biosciences, vol. 8, 654333. https://doi.org/10.3389/fmolb.2021.654333

APA

Ahmed, M. C., Skaanning, L. K., Jussupow, A., Newcombe, E. A., Kragelund, B. B., Camilloni, C., Langkilde, A. E., & Lindorff-Larsen, K. (2021). Refinement of α-Synuclein Ensembles Against SAXS Data: Comparison of Force Fields and Methods. Frontiers in Molecular Biosciences, 8, [654333]. https://doi.org/10.3389/fmolb.2021.654333

Vancouver

Ahmed MC, Skaanning LK, Jussupow A, Newcombe EA, Kragelund BB, Camilloni C et al. Refinement of α-Synuclein Ensembles Against SAXS Data: Comparison of Force Fields and Methods. Frontiers in Molecular Biosciences. 2021;8. 654333. https://doi.org/10.3389/fmolb.2021.654333

Author

Ahmed, Mustapha Carab ; Skaanning, Line K. ; Jussupow, Alexander ; Newcombe, Estella A. ; Kragelund, Birthe B. ; Camilloni, Carlo ; Langkilde, Annette E. ; Lindorff-Larsen, Kresten. / Refinement of α-Synuclein Ensembles Against SAXS Data : Comparison of Force Fields and Methods. In: Frontiers in Molecular Biosciences. 2021 ; Vol. 8.

Bibtex

@article{17dd021568194e6c9467f8b547950847,
title = "Refinement of α-Synuclein Ensembles Against SAXS Data: Comparison of Force Fields and Methods",
abstract = "The inherent flexibility of intrinsically disordered proteins (IDPs) makes it difficult to interpret experimental data using structural models. On the other hand, molecular dynamics simulations of IDPs often suffer from force-field inaccuracies, and long simulation times or enhanced sampling methods are needed to obtain converged ensembles. Here, we apply metainference and Bayesian/Maximum Entropy reweighting approaches to integrate prior knowledge of the system with experimental data, while also dealing with various sources of errors and the inherent conformational heterogeneity of IDPs. We have measured new SAXS data on the protein α-synuclein, and integrate this with simulations performed using different force fields. We find that if the force field gives rise to ensembles that are much more compact than what is implied by the SAXS data it is difficult to recover a reasonable ensemble. On the other hand, we show that when the simulated ensemble is reasonable, we can obtain an ensemble that is consistent with the SAXS data, but also with NMR diffusion and paramagnetic relaxation enhancement data.",
keywords = "intrinsically disordered protein, molecular dynamics simulation, NMR, protein, small-angle X-ray scattering",
author = "Ahmed, {Mustapha Carab} and Skaanning, {Line K.} and Alexander Jussupow and Newcombe, {Estella A.} and Kragelund, {Birthe B.} and Carlo Camilloni and Langkilde, {Annette E.} and Kresten Lindorff-Larsen",
note = "Funding Information: We thank A. Kikhney and C. Jeffries for assistance during data collection at the P12 SAXS beamline. We thank D. E. Shaw Research for sharing the molecular dynamics trajectories. Funding. We acknowledge support by a grant from the Lundbeck Foundation to the BRAINSTRUC Structural Biology Initiative (R155-2015-2666). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2021 Ahmed, Skaanning, Jussupow, Newcombe, Kragelund, Camilloni, Langkilde and Lindorff-Larsen.",
year = "2021",
doi = "10.3389/fmolb.2021.654333",
language = "English",
volume = "8",
journal = "Frontiers in Molecular Biosciences",
issn = "2296-889X",
publisher = "Frontiers Media",

}

RIS

TY - JOUR

T1 - Refinement of α-Synuclein Ensembles Against SAXS Data

T2 - Comparison of Force Fields and Methods

AU - Ahmed, Mustapha Carab

AU - Skaanning, Line K.

AU - Jussupow, Alexander

AU - Newcombe, Estella A.

AU - Kragelund, Birthe B.

AU - Camilloni, Carlo

AU - Langkilde, Annette E.

AU - Lindorff-Larsen, Kresten

N1 - Funding Information: We thank A. Kikhney and C. Jeffries for assistance during data collection at the P12 SAXS beamline. We thank D. E. Shaw Research for sharing the molecular dynamics trajectories. Funding. We acknowledge support by a grant from the Lundbeck Foundation to the BRAINSTRUC Structural Biology Initiative (R155-2015-2666). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © Copyright © 2021 Ahmed, Skaanning, Jussupow, Newcombe, Kragelund, Camilloni, Langkilde and Lindorff-Larsen.

PY - 2021

Y1 - 2021

N2 - The inherent flexibility of intrinsically disordered proteins (IDPs) makes it difficult to interpret experimental data using structural models. On the other hand, molecular dynamics simulations of IDPs often suffer from force-field inaccuracies, and long simulation times or enhanced sampling methods are needed to obtain converged ensembles. Here, we apply metainference and Bayesian/Maximum Entropy reweighting approaches to integrate prior knowledge of the system with experimental data, while also dealing with various sources of errors and the inherent conformational heterogeneity of IDPs. We have measured new SAXS data on the protein α-synuclein, and integrate this with simulations performed using different force fields. We find that if the force field gives rise to ensembles that are much more compact than what is implied by the SAXS data it is difficult to recover a reasonable ensemble. On the other hand, we show that when the simulated ensemble is reasonable, we can obtain an ensemble that is consistent with the SAXS data, but also with NMR diffusion and paramagnetic relaxation enhancement data.

AB - The inherent flexibility of intrinsically disordered proteins (IDPs) makes it difficult to interpret experimental data using structural models. On the other hand, molecular dynamics simulations of IDPs often suffer from force-field inaccuracies, and long simulation times or enhanced sampling methods are needed to obtain converged ensembles. Here, we apply metainference and Bayesian/Maximum Entropy reweighting approaches to integrate prior knowledge of the system with experimental data, while also dealing with various sources of errors and the inherent conformational heterogeneity of IDPs. We have measured new SAXS data on the protein α-synuclein, and integrate this with simulations performed using different force fields. We find that if the force field gives rise to ensembles that are much more compact than what is implied by the SAXS data it is difficult to recover a reasonable ensemble. On the other hand, we show that when the simulated ensemble is reasonable, we can obtain an ensemble that is consistent with the SAXS data, but also with NMR diffusion and paramagnetic relaxation enhancement data.

KW - intrinsically disordered protein

KW - molecular dynamics simulation

KW - NMR

KW - protein

KW - small-angle X-ray scattering

U2 - 10.3389/fmolb.2021.654333

DO - 10.3389/fmolb.2021.654333

M3 - Journal article

C2 - 33968988

AN - SCOPUS:85105396641

VL - 8

JO - Frontiers in Molecular Biosciences

JF - Frontiers in Molecular Biosciences

SN - 2296-889X

M1 - 654333

ER -

ID: 262899103