title: Transient helicity in intrinsically disordered Axin-1 studied by NMR spectroscopy and molecular dynamics simulations.
abstract: Many natural proteins are, as a whole or in part, intrinsically disordered. Frequently, such intrinsically disordered regions (IDRs) undergo a transition to a defined and often helical conformation upon binding to partner molecules. The intrinsic propensity of an IDR sequence to fold into a helical conformation already in the absence of a binding partner can have a decisive influence on the binding process and affinity. Using a combination of NMR spectroscopy and molecular dynamics (MD) simulations we have investigated the tendency of regions of Axin-1, an intrinsically disordered scaffolding protein of the WNT signaling pathway, to form helices in segments interacting with binding partners. Secondary chemical shifts from NMR measurements show an increased helical population in these regions. Systematic application of MD advanced sampling approaches on peptide segments of Axin-1 reproduces the experimentally observed tendency and allows insights into the distribution of segment conformations and free energies of helix formation. The results, however, were found to dependent on the force field water model. Recent water models specifically designed for IDRs significantly reduce the predicted helical content and do not improve the agreement with experiment.
authors.affiliation: Physik-Department, Technische Universität München, Garching, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Bomblies
authors.affiliation: Physik-Department, Technische Universität München, Garching, Germany.
authors.forename: Manuel Patrick
authors.initials: MP
authors.lastname: Luitz
authors.affiliation: Department Chemie, Technische Universität München, Garching, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Scanu
authors.affiliation: Institute of Structural Biology Helmholtz Zentrum München, Neuherberg, Germany.|Institute of Molecular Biology & Biochemistry Center of Molecular Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Tobias
authors.initials: T
authors.lastname: Madl
authors.affiliation: Physik-Department, Technische Universität München, Garching, Germany.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0001-5163-2663
authors.initials: M
authors.lastname: Zacharias
mesh_terms: D060466:Axin Protein / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D064267:Intrinsically Disordered Proteins; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D000072756:Protein Conformation, alpha-Helical; D013816:Thermodynamics
chemical_list: C555451:AXIN1 protein, human; D060466:Axin Protein; D064267:Intrinsically Disordered Proteins