title: NMR characterization of long-range order in intrinsically disordered proteins.
abstract: Intrinsically disordered proteins (IDPs) are predicted to represent a significant fraction of the human genome, and the development of meaningful molecular descriptions of these proteins remains a key challenge for contemporary structural biology. In order to describe the conformational behavior of IDPs, a molecular representation of the disordered state based on diverse sources of structural data that often exhibit complex and very different averaging behavior is required. In this study, we propose a combination of paramagnetic relaxation enhancements (PREs) and residual dipolar couplings (RDCs) to define both long-range and local structural features of IDPs in solution. We demonstrate that ASTEROIDS, an ensemble selection algorithm, faithfully reproduces intramolecular contacts, even in the presence of highly diffuse, ill-defined target interactions. We also show that explicit modeling of spin-label mobility significantly improves the reproduction of experimental PRE data, even in the case of highly disordered proteins. Prediction of the effects of transient long-range contacts on RDC profiles reveals that weak intramolecular interactions can induce a severe distortion of the profiles that compromises the description of local conformational sampling if it is not correctly taken into account. We have developed a solution to this problem that involves efficiently combining RDC and PRE data to simultaneously determine long-range and local structure in highly flexible proteins. This combined analysis is shown to be essential for the accurate interpretation of experimental data from alpha-synuclein, an important IDP involved in human neurodegenerative disease, confirming the presence of long-range order between distant regions in the protein.
authors.affiliation: Protein Dynamics and Flexibility, Institut de Biologie Structurale Jean-Pierre Ebel, CEA; CNRS; UJF UMR 5075, 41 Rue Jules Horowitz, Grenoble 38027, France.
authors.forename: Loïc
authors.initials: L
authors.lastname: Salmon
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Nodet
authors.forename: Valéry
authors.initials: V
authors.lastname: Ozenne
authors.forename: Guowei
authors.initials: G
authors.lastname: Yin
authors.forename: Malene Ringkjøbing
authors.initials: MR
authors.lastname: Jensen
authors.forename: Markus
authors.initials: M
authors.lastname: Zweckstetter
authors.forename: Martin
authors.initials: M
authors.lastname: Blackledge
mesh_terms: D055592:Biophysical Phenomena; D008280:Magnetics; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D015203:Reproducibility of Results; D012996:Solutions; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D012996:Solutions; D051844:alpha-Synuclein