title: Efficient construction of disordered protein ensembles in a Bayesian framework with optimal selection of conformations.
abstract: Constructing an accurate model for the thermally accessible states of an Intrinsically Disordered Protein (IDP) is a fundamental problem in structural biology. This problem requires one to consider a large number of conformations in order to ensure that the model adequately represents the range of structures that the protein can adopt. Typically, one samples a wide range of structures in an attempt to obtain an ensemble that agrees with some pre-specified set of experimental data. However, models that contain more structures than  the available experimental restraints are problematic as the large number of degrees of freedom in the ensemble leads to considerable uncertainty in the final model. We introduce a computationally efficient algorithm called Variational Bayesian Weighting with Structure Selection (VBWSS) for constructing a model for the ensemble of an IDP that contains a minimal number of conformations and, simultaneously, provides estimates for the uncertainty in properties calculated from the model. The algorithm is validated using reference ensembles and applied to construct an ensemble for the 140-residue IDP, monomeric α- synuclein.
authors.affiliation: Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, Massachusetts 02139-4307, United States. ckfisher@fas.harvard.edu
authors.forename: Charles K
authors.initials: CK
authors.lastname: Fisher
authors.forename: Orly
authors.initials: O
authors.lastname: Ullman
authors.forename: Collin M
authors.initials: CM
authors.lastname: Stultz
mesh_terms: D000465:Algorithms; D001499:Bayes Theorem; D019295:Computational Biology; D016001:Confidence Intervals; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D011506:Proteins / Q000737:chemistry*; D051844:alpha-Synuclein / Q000737:chemistry
chemical_list: D011506:Proteins; D051844:alpha-Synuclein