title: Characterization of the Free State Ensemble of the CoRNR Box Motif by Molecular Dynamics Simulations.
abstract: Intrinsically disordered proteins (IDPs) and regions are highly prevalent in eukaryotic proteomes, and like folded proteins, they perform essential biological functions. Interaction sites in folded proteins are generally formed by tertiary structures, whereas IDPs use short segments called linear motifs (LMs). Despite their short length and lack of stable structure, LMs may have considerable structural propensities, which often resemble bound-state conformations with targets. Structural data is crucial for understanding the molecular basis of protein interactions and development of targeted pharmaceuticals, but IDPs present considerable challenges to experimental techniques. As a result, IDPs are largely underrepresented in the Protein Data Bank. In the face of experimental challenges, molecular dynamics (MD) simulations have proven to be a useful tool for structural characterization of IDPs. Here, the free state ensemble of the nuclear receptor corepressor 1 (NCOR1) CoRNR box 3 motif, which is important for binding to nuclear receptors to control gene expression, is studied using MD simulations of a total of 8 μs. Transitions between disordered and α-helical conformations resembling a bound-state structure were observed throughout the trajectory, indicating that the motif may have a natural conformational bias toward bound-state structures. The data shows that the disordered and folded populations are separated by a low energy (4-6 kJ/mol) barrier, and the presence of off-pathway intermediates, leading to a C-terminally folded species that cannot efficiently transition into a completely folded conformation. Structural transitions and folding pathways within the free state ensemble were well-described by principal component analysis (PCA) of the peptide backbone dihedral angles, with the analysis providing insight for increasing structural homogeneity of the ensemble.
authors.affiliation: Department of Biochemistry, The University of Western Ontario , London, Ontario N6A 5C1, Canada.
authors.forename: Elio A
authors.initials: EA
authors.lastname: Cino
authors.affiliation: Department of Biochemistry, The University of Western Ontario , London, Ontario N6A 5C1, Canada.
authors.forename: Wing-Yiu
authors.initials: WY
authors.lastname: Choy
authors.affiliation: Department of Mathematics and Computer Science & the Institute for Complex Molecular Systems, Eindhoven University of Technology , P.O. Box 513, MetaForum, Eindhoven 5600 MB, The Netherlands.
authors.forename: Mikko
authors.initials: M
authors.lastname: Karttunen
mesh_terms: D006801:Humans; D056004:Molecular Dynamics Simulation; D056971:Nuclear Receptor Co-Repressor 1 / Q000737:chemistry*; D025341:Principal Component Analysis
chemical_list: C539127:NCOR1 protein, human; D056971:Nuclear Receptor Co-Repressor 1