Modeling Intrinsically Disordered Proteins with Bayesian Statistics

详细信息    查看全文

• 作者：Charles K. Fisher ; Austin Huang ; Collin M. Stultz
• 刊名：Journal of the American Chemical Society
• 出版年：2010
• 出版时间：October 27, 2010
• 年：2010
• 卷：132
• 期：42
• 页码：14919-14927
• 全文大小：280K
• 年卷期：v.132,no.42(October 27, 2010)
• ISSN：1520-5126

文摘

The characterization of intrinsically disordered proteins is challenging because accurate models of these systems require a description of both their thermally accessible conformers and the associated relative stabilities or weights. These structures and weights are typically chosen such that calculated ensemble averages agree with some set of prespecified experimental measurements; however, the large number of degrees of freedom in these systems typically leads to multiple conformational ensembles that are degenerate with respect to any given set of experimental observables. In this work we demonstrate that estimates of the relative stabilities of conformers within an ensemble are often incorrect when one does not account for the underlying uncertainty in the estimates themselves. Therefore, we present a method for modeling the conformational properties of disordered proteins that estimates the uncertainty in the weights of each conformer. The Bayesian weighting (BW) formalism incorporates information from both experimental data and theoretical predictions to calculate a probability density over all possible ways of weighting the conformers in the ensemble. This probability density is then used to estimate the values of the weights. A unique and powerful feature of the approach is that it provides a built-in error measure that allows one to assess the accuracy of the ensemble. We validate the approach using reference ensembles constructed from the five-residue peptide met-enkephalin and then apply the BW method to construct an ensemble of the K18 isoform of the tau protein. Using this ensemble, we indentify a specific pattern of long-range contacts in K18 that correlates with the known aggregation properties of the sequence.