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

Henriques, João LU ; Arleth, Lise; Lindorff-Larsen, Kresten and Skepö, Marie LU (2018) In Journal of Molecular Biology 430(16). p.2521-2539
Abstract

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,... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
conformational ensemble, hydration shell, intrinsically disordered protein, molecular dynamics, SAXS
in
Journal of Molecular Biology
volume
430
issue
16
pages
2521 - 2539
publisher
Elsevier
external identifiers
  • scopus:85044319160
ISSN
0022-2836
DOI
10.1016/j.jmb.2018.03.002
language
English
LU publication?
yes
id
8a8ea947-6064-4561-a106-ec8ec94e5661
date added to LUP
2018-04-10 07:31:24
date last changed
2019-01-14 14:57:39
@article{8a8ea947-6064-4561-a106-ec8ec94e5661,
  abstract     = {<p>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.</p>},
  author       = {Henriques, João and Arleth, Lise and Lindorff-Larsen, Kresten and Skepö, Marie},
  issn         = {0022-2836},
  keyword      = {conformational ensemble,hydration shell,intrinsically disordered protein,molecular dynamics,SAXS},
  language     = {eng},
  number       = {16},
  pages        = {2521--2539},
  publisher    = {Elsevier},
  series       = {Journal of Molecular Biology},
  title        = {On the Calculation of SAXS Profiles of Folded and Intrinsically Disordered Proteins from Computer Simulations},
  url          = {http://dx.doi.org/10.1016/j.jmb.2018.03.002},
  volume       = {430},
  year         = {2018},
}