Refinement of α-Synuclein Ensembles Against SAXS Data: Comparison of Force Fields and Methods
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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 journal › Journal article › peer-review
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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