Improving fold recognition of protein threading by experimental distance constraints
Mario Albrecht*, Daniel Hanisch, Ralf Zimmer and Thomas Lengauer
Fraunhofer Institute for Algorithms and Scientific Computing (SCAI), Schloss Birlinghoven, D-53754 Sankt Augustin, Germany
We present a comprehensive analysis of methods for improving the fold recognition rate of the threading approach to protein structure prediction by the utilization of few additional distance constraints. The distance constraints between protein residues may be obtained by experiments such as mass spectrometry or NMR spectroscopy. We applied a post-filtering step with new scoring functions incorporating measures of constraint satisfaction to ranking lists of 123D threading alignments. The detailed analysis of the results on a small representative benchmark set show that the fold recognition rate can be improved significantly by up to 30% from about 54%-65% to 77%-84%, approaching the maximal attainable performance of 90% estimated by structural superposition alignments. This gain in performance adds about 10% to the recognition rate already achieved in our previous study with cross-link constraints only. Additional recent results on a larger benchmark set involving a confidence function for threading predictions also indicate notable improvements by our combined approach, which should be particularly valuable for rapid structure determination and validation of protein models.
Key words: protein threading, fold recognition, structure prediction, experimental data, distance constraints, cross-linking reagents, mass spectrometry, NOE restraints, NMR