title: Determination of the free energy landscape of alpha-synuclein using spin label nuclear magnetic resonance measurements.
abstract: Natively unfolded proteins present a challenge for structure determination because they populate highly heterogeneous ensembles of conformations. A useful source of structural information about these states is provided by paramagnetic relaxation enhancement measurements by nuclear magnetic resonance spectroscopy, from which long-range interatomic distances can be estimated. Here we describe a method for using such distances as restraints in molecular dynamics simulations to obtain a mapping of the free energy landscapes of natively unfolded proteins. We demonstrate the method in the case of alpha-synuclein and validate the results by a comparison with electron transfer measurements. Our findings indicate that our procedure provides an accurate estimate of the relative statistical weights of the different conformations populated by alpha-synuclein in its natively unfolded state.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Allison
authors.forename: Peter
authors.initials: P
authors.lastname: Varnai
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
mesh_terms: D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008722:Methods; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011489:Protein Denaturation; D013113:Spin Labels; D013816:Thermodynamics; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D013113:Spin Labels; D051844:alpha-Synuclein