On the Calculation of SAXS Profiles of Folded and Intrinsically Disordered Proteins from Computer Simulations |
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Authors: | João Henriques Lise Arleth Kresten Lindorff-Larsen Marie Skepö |
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Affiliation: | 1. Division of Theoretical Chemistry, Department of Chemistry, Lund University, Kemicentrum, PO Box 124, S-221 00 Lund, Sweden;2. Structural Biology and NMR Laboratory & Linderstrøm–Lang Centre for Protein Science, Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark;3. Structural Biophysics, Section for Neutron and X-ray Science, Niels Bohr Institute, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen Ø, Denmark |
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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, 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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Keywords: | SAXS intrinsically disordered protein hydration shell molecular dynamics conformational ensemble SAXS small-angle X-ray scattering IDPs intrinsically disordered proteins MD molecular dynamics HEWL hen egg-white lysozyme RDFs radial distribution functions IFT indirect Fourier transformation |
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