title: Molecular simulations of the fluctuating conformational dynamics of intrinsically disordered proteins.
abstract: Intrinsically disordered proteins (IDPs) do not possess well-defined three-dimensional structures in solution under physiological conditions. We develop all-atom, united-atom, and coarse-grained Langevin dynamics simulations for the IDP α-synuclein that include geometric, attractive hydrophobic, and screened electrostatic interactions and are calibrated to the inter-residue separations measured in recent single-molecule fluorescence energy transfer (smFRET) experiments. We find that α-synuclein is disordered, with conformational statistics that are intermediate between random walk and collapsed globule behavior. An advantage of calibrated molecular simulations over constraint methods is that physical forces act on all residues, not only on residue pairs that are monitored experimentally, and these simulations can be used to study oligomerization and aggregation of multiple α-synuclein proteins that may precede amyloid formation.
authors.affiliation: Department of Physics, Yale University, New Haven, Connecticut 06520-8120, USA.
authors.forename: W Wendell
authors.initials: WW
authors.lastname: Smith
authors.forename: Carl F
authors.initials: CF
authors.lastname: Schreck
authors.forename: Nabeem
authors.initials: N
authors.lastname: Hashem
authors.forename: Sherwin
authors.initials: S
authors.lastname: Soltani
authors.forename: Abhinav
authors.initials: A
authors.lastname: Nath
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rhoades
authors.forename: Corey S
authors.initials: CS
authors.lastname: O'Hern
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D001703:Biophysics / Q000379:methods*; D002138:Calibration; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015233:Models, Statistical; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D010300:Parkinson Disease / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D051844:alpha-Synuclein / Q000737:chemistry*
chemical_list: D000682:Amyloid; D011506:Proteins; D012997:Solvents; D051844:alpha-Synuclein