BCL::SAXS: GPU accelerated Debye method for computation of small angle X-ray scattering profiles

Abstract

Small angle X-ray scattering (SAXS) is an experimental technique used for structural characterization of macromolecules in solution. Here, we introduce BCL::SAXS – an algorithm designed to replicate SAXS profiles from rigid protein models at different levels of detail. We first show our derivation of BCL::SAXS and compare our results with the experimental scattering profile of Hen Egg White Lysozyme. Using this protein we show how to generate SAXS profiles representing: 1) complete models, 2) models with approximated side chain coordinates, and 3) models with approximated side chain and loop region coordinates. We evaluated the ability of SAXS profiles to identify a correct protein topology from a non-redundant benchmark set of proteins. We find that complete SAXS profiles can be used to identify the correct protein by receiver operating characteristic (ROC) analysis with an area under the curve (AUC) > 99%. We show how our approximation of loop coordinates between secondary structure elements improves protein recognition by SAXS for protein models without loop regions and side chains. Agreement with SAXS data is a necessary but not sufficient condition for structure determination. We conclude that experimental SAXS data can be used as a filter to exclude protein models with large structural differences from the native.

Iterative Molecular Dynamics–Rosetta Membrane Protein Structure Refinement Guided by Cryo-EM Densities

“…These approaches combine low to medium-resolution experimental data from heterogeneous experimental techniques with computational modeling methods 50, 51 . Experimental data has been used from a broad range of sources including NMR spectroscopy 52–54 , fluorescence resonance energy transfer microscopy (FRET) 55 , electron paramagnetic resonance (EPR) 56, 57 , cryo-EM 58–60 , small angle X-ray scattering (SAXS) 61, 62 , small angle neutron scattering (SANS) 63 and mass spectroscopy 64–66 . These sparse experimental restraints used in combination with computational methods have shown to considerably improve macromolecular structure prediction and refinement 53, 60, 67 .…”

Structure and Dynamics of Type III Secretion Effector Protein ExoU As determined by SDSL-EPR Spectroscopy in Conjunction with De Novo Protein Folding

“… 15 However, it was demonstrated that incorporation of limited experimental data significantly mitigates problems in model discrimination. 16 − 19 The Rosetta method 20 , 21 was used to add atomic detail and energy-optimize the final models.…”

Federating Structural Models and Data: Outcomes from A Workshop on Archiving Integrative Structures

“…The Biochemical Library (BCL) program models proteins as assemblies of secondary structure elements (Karakas et al, 2012). The BCL can simultaneously use experimental restraints from 3DEM (Lindert et al, 2009), NMR (Weiner et al, 2014), EPR (Fischer et al, 2015), CX-MS (Hofmann et al, 2015), and SAS (Putnam et al, 2015) experiments. The rationale for replacing flexible loop regions with a loop closure constraint is to substantially reduce the conformational space of a protein, correspondingly reducing the sampling challenge.…”