title: Kirkwood-Buff Approach Rescues Overcollapse of a Disordered Protein in Canonical Protein Force Fields.
abstract: Understanding the function of intrinsically disordered proteins is intimately related to our capacity to correctly sample their conformational dynamics. So far, a gap between experimentally and computationally derived ensembles exists, as simulations show overcompacted conformers. Increasing evidence suggests that the solvent plays a crucial role in shaping the ensembles of intrinsically disordered proteins and has led to several attempts to modify water parameters and thereby favor protein-water over protein-protein interactions. This study tackles the problem from a different perspective, which is the use of the Kirkwood-Buff theory of solutions to reproduce the correct conformational ensemble of intrinsically disordered proteins (IDPs). A protein force field recently developed on such a basis was found to be highly effective in reproducing ensembles for a fragment from the FG-rich nucleoporin 153, with dimensions matching experimental values obtained from small-angle X-ray scattering and single molecule FRET experiments. Kirkwood-Buff theory presents a complementary and fundamentally different approach to the recently developed four-site TIP4P-D water model, both of which can rescue the overcollapse observed in IDPs with canonical protein force fields. As such, our study provides a new route for tackling the deficiencies of current protein force fields in describing protein solvation.
authors.affiliation: †HITS-Heidelberg Institut for Theoretical Studies, Schloß-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany.|‡IWR-Interdisciplinary Center for Scientific Computing, Im Neuenheimer Feld 368, 69120, Heidelberg, Germany.
authors.forename: Davide
authors.initials: D
authors.lastname: Mercadante
authors.affiliation: ∥EMBL-European Molecular Biology Laboratory, Meyerhofstraße 1, 69117, Heidelberg, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Milles
authors.affiliation: §EMBL-European Molecular Biology Laboratory, Notkestraße 85, 22607, Hamburg, Germany.|∥EMBL-European Molecular Biology Laboratory, Meyerhofstraße 1, 69117, Heidelberg, Germany.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Fuertes
authors.affiliation: §EMBL-European Molecular Biology Laboratory, Notkestraße 85, 22607, Hamburg, Germany.
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
authors.affiliation: ∥EMBL-European Molecular Biology Laboratory, Meyerhofstraße 1, 69117, Heidelberg, Germany.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Lemke
authors.affiliation: †HITS-Heidelberg Institut for Theoretical Studies, Schloß-Wolfsbrunnenweg 35, 69118, Heidelberg, Germany.|‡IWR-Interdisciplinary Center for Scientific Computing, Im Neuenheimer Feld 368, 69120, Heidelberg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Gräter
mesh_terms: D004926:Escherichia coli; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D028861:Nuclear Pore Complex Proteins / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D053838:Scattering, Small Angle; D012996:Solutions; D014867:Water / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D064267:Intrinsically Disordered Proteins; C079377:NUP153 protein, human; D028861:Nuclear Pore Complex Proteins; D012996:Solutions; D014867:Water