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Title: Native state of complement protein C3d analysed via hydrogen exchange and conformational sampling

Authors: Didier Devaurs; Malvina Papanastasiou; Dinler A. Antunes; Jayvee R. Abella; Mark Moll; Daniel Ricklin; John D. Lambris; Lydia E. Kavraki

Addresses: Department of Computer Science, Rice University, Houston, TX, 77005, USA ' Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Broad Institute of MIT & Harvard, Cambridge, MA, 02142, USA ' Department of Computer Science, Rice University, Houston, TX, 77005, USA ' Department of Computer Science, Rice University, Houston, TX, 77005, USA ' Department of Computer Science, Rice University, Houston, TX, 77005, USA ' Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Department of Pharmaceutical Sciences, University of Basel, Basel, CH-4056, Switzerland ' Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA ' Department of Computer Science, Rice University, Houston, TX, 77005, USA

Abstract: Hydrogen/deuterium exchange detected by mass spectrometry (HDX-MS) provides valuable information on protein structure and dynamics. Although HDX-MS data is often interpreted using crystal structures, it was suggested that conformational ensembles produced by molecular dynamics simulations yield more accurate interpretations. In this paper, we analyse the complement protein C3d by performing an HDX-MS experiment, and evaluate several interpretation methodologies using an existing prediction model to derive HDX-MS data from protein structure. To interpret and refine C3d's HDX-MS data, we look for a conformation (or conformational ensemble) of C3d that allows computationally replicating this data. We confirm that crystal structures are not a good choice and suggest that conformational ensembles produced by molecular dynamics simulations might not always be satisfactory either. Finally, we show that coarse-grained conformational sampling of C3d produces a conformation from which its HDX-MS data can be replicated and refined.

Keywords: complement protein C3d; hydrogen exchange; mass spectrometry; protein conformational sampling; coarse-grained conformational sampling; native state; X-ray crystallography; molecular dynamics; protein structures; conformational ensembles.

DOI: 10.1504/IJCBDD.2018.090834

International Journal of Computational Biology and Drug Design, 2018 Vol.11 No.1/2, pp.90 - 113

Available online: 24 Mar 2018 *

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