Using inferred residue contacts to distinguish between correct and incorrect protein models

By ChristopherA. Miller, David S. Eisenberg. 2008

51 citations recorded by the source corpus.

Motivation: The de novo prediction of 3D protein structure is enjoying a period of dramatic improvements. Often, a remaining difficulty is to select the model closest to the true structure from a group of low-energy candidates. To what extent can inter-residue contact predictions from multiple sequence alignments, information which is orthogonal to that used in most structure prediction algorithms, be used to identify those models most similar to the native protein structure? Results: We present a Bayesian inference procedure to identify residue pairs that are spatially proximal in a protein structure. The method takes as input a multiple sequence alignment, and outputs an accurate posterior probability of proximity for each residue pair. We exploit a recent metagenomic sequencing project to create large, diverse and informative multiple sequence alignments for a test set of 1656 known protein structures. The method infers spatially proximal residue pairs in this test set with good accuracy: top-ranked predictions achieve an average accuracy of 38% (for an average 21-fold improvement over random predictions) in cross-validation tests. Notably, the accuracy of predicted 3D models generated by a range of structure prediction algorithms strongly correlates with how well the models satisfy probable residue contacts inferred via our method. This correlation allows for confident rejection of incorrect structural models. Availability: An implementation of the method is freely available at http://www.doe-mbi.ucla.edu/services Contact: david@mbi.ucla.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Subfields: Materials Chemistry, Molecular Biology

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Citations in the corpus

Protein 3D Structure Computed from Evolutionary Sequence Variation (2011, background): “residues in spatial proximity may co-evolve across a protein family [2,3].”
3D structures of membrane proteins from genomic sequencing (2012, neutral): “…a small number of models are generated, we devised a ranking scheme based on simple intuitive requirements for membrane proteins, such as satisfaction of unused constraints (adapted from Miller and Eisenberg, 2008),predictedsecondarystructure,andpredictedlipidexposureagreement in the folded models.”
3D Protein Structure Predicted from Sequence (2011, unknown): “In particular, to maintain energetically favorable interactions, residues in spatial proximity tend to co-‐evolve across a protein family [2,3].”
Disentangling Direct from Indirect Co-Evolution of Residues in Protein Alignments (2010, background): “Ultimately the most satisfying approach would be to combine our approach with direct structural modeling, i.e. somewhat along the lines of the approach taken in [34].”
De Novo Structure Prediction of Globular Proteins Aided by Sequence Variation-Derived Contacts (2014, background): “Examples of contact prediction range from distinguishing between correct and incorrect protein models [5], identifying direct residue contacts in protein-protein complexes [6] or as part of empirical force field for molecular dynamics simulations of protein folding [7].”