High-density chemical cross-linking for modeling protein interactions

We combine several orthogonal cross-linking chemistries as well as improvements in search algorithms, statistical analysis and computational cost to achieve coverage of one unique cross-linked position pair for every 7 amino acids at a 1% false discovery rate. This is accomplished without any peptide-level fractionation, enrichment, or isotopic labeling. We apply our methods to model the complex between a carbonic anhydrase (CA) and its protein inhibitor, as well as the yeast proteasome