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.
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