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Title: Theoretical modeling of multiprotein complexes by iSPOT: Integration of small-angle X-ray scattering, hydroxyl radical footprinting, and computational docking

Abstract

Structural determination of protein-protein complexes such as multidomain nuclear receptors has been challenging for high-resolution structural techniques. Here, we present a combined use of multiple biophysical methods, termed iSPOT, an integration of shape information from small-angle X-ray scattering (SAXS), protection factors probed by hydroxyl radical footprinting, and a large series of computationally docked conformations from rigid-body or molecular dynamics (MD) simulations. Specifically tested on two model systems, the power of iSPOT is demonstrated to accurately predict the structures of a large protein-protein complex (TGFβ-FKBP12) and a multidomain nuclear receptor homodimer (HNF-4α), based on the structures of individual components of the complexes. Although neither SAXS nor footprinting alone can yield an unambiguous picture for each complex, the combination of both, seamlessly integrated in iSPOT, narrows down the best-fit structures that are about 3.2 Å and 4.2 Å in RMSD from their corresponding crystal structures, respectively. Furthermore, this proof-of-principle study based on the data synthetically derived from available crystal structures shows that the iSPOT—using either rigid-body or MD-based flexible docking—is capable of overcoming the shortcomings of standalone computational methods, especially for HNF-4α. Here, by taking advantage of the integration of SAXS-based shape information and footprinting-based protection/accessibility as well as computational docking, thismore » iSPOT platform is set to be a powerful approach towards accurate integrated modeling of many challenging multiprotein complexes.« less

Authors:
 [1];  [1];  [2];  [1]
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  1. Case Western Reserve Univ., Cleveland, OH (United States)
  2. McGill Univ., Montreal, QC (Canada)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Inst. of Health
OSTI Identifier:
1352232
Grant/Contract Number:  
R01GM114056
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Structural Biology
Additional Journal Information:
Journal Volume: 196; Journal Issue: 3; Journal ID: ISSN 1047-8477
Publisher:
Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Integration; SAXS; Footprinting; Modeling

Citation Formats

Huang, Wei, Ravikumar, Krishnakumar M., Parisien, Marc, and Yang, Sichun. Theoretical modeling of multiprotein complexes by iSPOT: Integration of small-angle X-ray scattering, hydroxyl radical footprinting, and computational docking. United States: N. p., 2016. Web. doi:10.1016/j.jsb.2016.08.001.
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Huang, Wei, Ravikumar, Krishnakumar M., Parisien, Marc, & Yang, Sichun. Theoretical modeling of multiprotein complexes by iSPOT: Integration of small-angle X-ray scattering, hydroxyl radical footprinting, and computational docking. United States. https://doi.org/10.1016/j.jsb.2016.08.001
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Huang, Wei, Ravikumar, Krishnakumar M., Parisien, Marc, and Yang, Sichun. Tue . "Theoretical modeling of multiprotein complexes by iSPOT: Integration of small-angle X-ray scattering, hydroxyl radical footprinting, and computational docking". United States. https://doi.org/10.1016/j.jsb.2016.08.001. https://www.osti.gov/servlets/purl/1352232.
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@article{osti_1352232,
title = {Theoretical modeling of multiprotein complexes by iSPOT: Integration of small-angle X-ray scattering, hydroxyl radical footprinting, and computational docking},
author = {Huang, Wei and Ravikumar, Krishnakumar M. and Parisien, Marc and Yang, Sichun},
abstractNote = {Structural determination of protein-protein complexes such as multidomain nuclear receptors has been challenging for high-resolution structural techniques. Here, we present a combined use of multiple biophysical methods, termed iSPOT, an integration of shape information from small-angle X-ray scattering (SAXS), protection factors probed by hydroxyl radical footprinting, and a large series of computationally docked conformations from rigid-body or molecular dynamics (MD) simulations. Specifically tested on two model systems, the power of iSPOT is demonstrated to accurately predict the structures of a large protein-protein complex (TGFβ-FKBP12) and a multidomain nuclear receptor homodimer (HNF-4α), based on the structures of individual components of the complexes. Although neither SAXS nor footprinting alone can yield an unambiguous picture for each complex, the combination of both, seamlessly integrated in iSPOT, narrows down the best-fit structures that are about 3.2 Å and 4.2 Å in RMSD from their corresponding crystal structures, respectively. Furthermore, this proof-of-principle study based on the data synthetically derived from available crystal structures shows that the iSPOT—using either rigid-body or MD-based flexible docking—is capable of overcoming the shortcomings of standalone computational methods, especially for HNF-4α. Here, by taking advantage of the integration of SAXS-based shape information and footprinting-based protection/accessibility as well as computational docking, this iSPOT platform is set to be a powerful approach towards accurate integrated modeling of many challenging multiprotein complexes.},
doi = {10.1016/j.jsb.2016.08.001},
journal = {Journal of Structural Biology},
number = 3,
volume = 196,
place = {United States},
year = {Tue Aug 02 00:00:00 EDT 2016},
month = {Tue Aug 02 00:00:00 EDT 2016}
}
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https://doi.org/10.1016/j.jsb.2016.08.001
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