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 alpha-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.

Refinement of α-Synuclein Ensembles Against SAXS Data : Comparison of Force Fields and Methods / M.C. Ahmed, L.K. Skaanning, A. Jussupow, E.A. Newcombe, B.B. Kragelund, C. Camilloni, A.E. Langkilde, K. Lindorff-Larsen. - In: FRONTIERS IN MOLECULAR BIOSCIENCES. - ISSN 2296-889X. - 8(2021), pp. 654333.1-654333.13.

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

C. Camilloni;
2021

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 alpha-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.
small-angle X-ray scattering; molecular dynamics simulation; NMR; protein; intrinsically disordered protein
Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin)
Article (author)
File in questo prodotto:
File Dimensione Formato  
fmolb-08-654333.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 5.46 MB
Formato Adobe PDF
5.46 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/842199
Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 11
  • ???jsp.display-item.citation.isi??? 12
social impact