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Photo Marie Skepö

Marie Skepö

Professor

Photo Marie Skepö

On the Calculation of SAXS Profiles of Folded and Intrinsically Disordered Proteins from Computer Simulations

Author

  • João Henriques
  • Lise Arleth
  • Kresten Lindorff-Larsen
  • Marie Skepö

Summary, in English

Solution techniques such as small-angle X-ray scattering (SAXS) play a central role in structural studies of intrinsically disordered proteins (IDPs); yet, due to low resolution, it is generally necessary to combine SAXS with additional experimental sources of data and to use molecular simulations. Computational methods for the calculation of theoretical SAXS intensity profiles can be separated into two groups, depending on whether the solvent is modeled implicitly as continuous electron density or considered explicitly. The former offers reduced computational cost but requires the definition of a number of free parameters to account for, for example, the excess density of the solvation layer. Overfitting can thus be an issue, particularly when the structural ensemble is unknown. Here, we investigate and show how small variations of the contrast of the hydration shell, δρ, severely affect the outcome, analysis and interpretation of computed SAXS profiles for folded and disordered proteins. For both the folded and disordered proteins studied here, using a default δρ may, in some cases, result in the calculation of non-representative SAXS profiles, leading to an overestimation of their size and a misinterpretation of their structural nature. The solvation layer of the different IDP simulations also impacts their size estimates differently, depending on the protein force field used. The same is not true for the folded protein simulations, suggesting differences in the solvation of the two classes of proteins, and indicating that different force fields optimized for IDPs may cause expansion of the polypeptide chain through different physical mechanisms.

Department/s

  • Computational Chemistry
  • eSSENCE: The e-Science Collaboration

Publishing year

2018

Language

English

Pages

2521-2539

Publication/Series

Journal of Molecular Biology

Volume

430

Issue

16

Document type

Journal article

Publisher

Elsevier

Topic

  • Biological Sciences

Keywords

  • conformational ensemble
  • hydration shell
  • intrinsically disordered protein
  • molecular dynamics
  • SAXS

Status

Published

ISBN/ISSN/Other

  • ISSN: 0022-2836