title: Coarse-Grained Conformational Sampling of Protein Structure Improves the Fit to Experimental Hydrogen-Exchange Data.
abstract: Monitoring hydrogen/deuterium exchange (HDX) undergone by a protein in solution produces experimental data that translates into valuable information about the protein's structure. Data produced by HDX experiments is often interpreted using a crystal structure of the protein, when available. However, it has been shown that the correspondence between experimental HDX data and crystal structures is often not satisfactory. This creates difficulties when trying to perform a structural analysis of the HDX data. In this paper, we evaluate several strategies to obtain a conformation providing a good fit to the experimental HDX data, which is a premise of an accurate structural analysis. We show that performing molecular dynamics simulations can be inadequate to obtain such conformations, and we propose a novel methodology involving a coarse-grained conformational sampling approach instead. By extensively exploring the intrinsic flexibility of a protein with this approach, we produce a conformational ensemble from which we extract asingleconformation providing a good fit to the experimental HDX data. We successfully demonstrate the applicability of our method to four small and medium-sized proteins.
authors.affiliation: Department of Computer Science, Rice University Houston, TX, USA.
authors.forename: Didier
authors.initials: D
authors.lastname: Devaurs
authors.affiliation: Department of Computer Science, Rice University Houston, TX, USA.
authors.forename: Dinler A
authors.initials: DA
authors.lastname: Antunes
authors.affiliation: Department of Pathology and Laboratory Medicine, University of PennsylvaniaPhiladelphia, PA, USA; Broad Institute of MIT & HarvardCambridge, MA, USA.
authors.forename: Malvina
authors.initials: M
authors.lastname: Papanastasiou
authors.affiliation: Department of Computer Science, Rice University Houston, TX, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Moll
authors.affiliation: Department of Pathology and Laboratory Medicine, University of PennsylvaniaPhiladelphia, PA, USA; Department of Pharmaceutical Sciences, University of BaselBasel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ricklin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Philadelphia, PA, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.affiliation: Department of Computer Science, Rice University Houston, TX, USA.
authors.forename: Lydia E
authors.initials: LE
authors.lastname: Kavraki
keywords: X-ray crystallography; coarse-grained conformational sampling; experimental data fitting; hydrogen/deuterium exchange; mass spectrometry; molecular dynamics; nuclear magnetic resonance spectroscopy; protein conformational sampling