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Open Access Research article

Robust probabilistic superposition and comparison of protein structures

Martin Mechelke1 and Michael Habeck12*

Author Affiliations

1 Department of Protein Evolution, Max-Planck-Institute for Developmental Biology, Spemannstr. 35, 72076 Tübingen, Germany

2 Department of Empirical Inference, Max-Planck-Institute for Biological Cybernetics, Spemannstr. 38, 72076 Tübingen, Germany

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BMC Bioinformatics 2010, 11:363  doi:10.1186/1471-2105-11-363

Published: 1 July 2010

Abstract

Background

Protein structure comparison is a central issue in structural bioinformatics. The standard dissimilarity measure for protein structures is the root mean square deviation (RMSD) of representative atom positions such as α-carbons. To evaluate the RMSD the structures under comparison must be superimposed optimally so as to minimize the RMSD. How to evaluate optimal fits becomes a matter of debate, if the structures contain regions which differ largely - a situation encountered in NMR ensembles and proteins undergoing large-scale conformational transitions.

Results

We present a probabilistic method for robust superposition and comparison of protein structures. Our method aims to identify the largest structurally invariant core. To do so, we model non-rigid displacements in protein structures with outlier-tolerant probability distributions. These distributions exhibit heavier tails than the Gaussian distribution underlying standard RMSD minimization and thus accommodate highly divergent structural regions. The drawback is that under a heavy-tailed model analytical expressions for the optimal superposition no longer exist. To circumvent this problem we work with a scale mixture representation, which implies a weighted RMSD. We develop two iterative procedures, an Expectation Maximization algorithm and a Gibbs sampler, to estimate the local weights, the optimal superposition, and the parameters of the heavy-tailed distribution. Applications demonstrate that heavy-tailed models capture differences between structures undergoing substantial conformational changes and can be used to assess the precision of NMR structures. By comparing Bayes factors we can automatically choose the most adequate model. Therefore our method is parameter-free.

Conclusions

Heavy-tailed distributions are well-suited to describe large-scale conformational differences in protein structures. A scale mixture representation facilitates the fitting of these distributions and enables outlier-tolerant superposition.