title: Experimental Inferential Structure Determination of Ensembles for Intrinsically Disordered Proteins.
abstract: We develop a Bayesian approach to determine the most probable structural ensemble model from candidate structures for intrinsically disordered proteins (IDPs) that takes full advantage of NMR chemical shifts and J-coupling data, their known errors and variances, and the quality of the theoretical back-calculation from structure to experimental observables. Our approach differs from previous formulations in the optimization of experimental and back-calculation nuisance parameters that are treated as random variables with known distributions, as opposed to structural or ensemble weight optimization or use of a reference ensemble. The resulting experimental inferential structure determination (EISD) method is size extensive with O(N) scaling, with N = number of structures, that allows for the rapid ranking of large ensemble data comprising tens of thousands of conformations. We apply the EISD approach on singular folded proteins and a corresponding set of ∼25 000 misfolded states to illustrate the problems that can arise using Boltzmann weighted priors. We then apply the EISD method to rank IDP ensembles most consistent with the NMR data and show that the primary error for ranking or creating good IDP ensembles resides in the poor back-calculation from structure to simulated experimental observable. We show that a reduction by a factor of 3 in the uncertainty of the back-calculation error can improve the discrimination among qualitatively different IDP ensembles for the amyloid-beta peptide.
authors.affiliation: Department of Chemistry, ‡Department of Bioengineering, §Department of Chemical and Biomolecular Engineering, ∥Chemical Sciences Division, Lawrence Berkeley National Laboratory, University of California , Berkeley, California 94720, United States.
authors.forename: David H
authors.initials: DH
authors.lastname: Brookes
authors.affiliation: Department of Chemistry, ‡Department of Bioengineering, §Department of Chemical and Biomolecular Engineering, ∥Chemical Sciences Division, Lawrence Berkeley National Laboratory, University of California , Berkeley, California 94720, United States.
authors.forename: Teresa
authors.initials: T
authors.lastname: Head-Gordon
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry; D001499:Bayes Theorem; D064267:Intrinsically Disordered Proteins / Q000737:chemistry*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D016229:Amyloid beta-Peptides; D064267:Intrinsically Disordered Proteins