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Cross-Link Guided Molecular Modeling with ROSETTA.

Type Information
Nr 37 (Research article)
Authors Kahraman, Abdullah; Herzog, Franz; Leitner, Alexander; Rosenberger, George; Aebersold, Ruedi; Malmström, Lars
Title Cross-Link Guided Molecular Modeling with ROSETTA.
Journal PLoS One (2013) 8 e73411
DOI 10.1371/journal.pone.0073411
Citations 126 citations (journal impact: 3.53)
Abstract Chemical cross-links identified by mass spectrometry generate distance restraints that reveal low-resolution structural information on proteins and protein complexes. The technology to reliably generate such data has become mature and robust enough to shift the focus to the question of how these distance restraints can be best integrated into molecular modeling calculations. Here we introduce three workflows for incorporating distance restraints generated by chemical cross-linking and mass spectrometry into ROSETTA protocols for comparative and de novo modeling and protein-protein docking. We demonstrate that the cross-link validation and visualization software Xwalk facilitates successful cross-link data integration. Besides the protocols we introduce XLdb a database of chemical cross-links from 14 different publications with 506 intra-protein and 62 inter-protein cross-links where each cross-link can be mapped on an experimental structure from the Protein Data Bank. Finally we demonstrate on a protein-protein docking reference data set the impact of virtual cross-links on protein docking calculations and show that an inter-protein cross-link can reduce on average the RMSD of a docking prediction by 5.0 . The methods and results presented here provide guidelines for the effective integration of chemical cross-link data in molecular modeling calculations and should advance the structural analysis of particularly large and transient protein complexes via hybrid structural biology methods.
Synopsis We describe how to guide protein-protein docking simulations using distance constraints generated by mass spectrometry.