How do we use protein chemistry to capture complex organization and topography, and what is the best way to measure these context-sensitive chemistries from trace-level cellular extracts? Our goal is to generate rich sets of restraint data that can be used to model both individual proteins and ultralarge protein complexes and networks. We explore novel strategies in protein crosslinking mass spectrometry (XL-MS) to produce precise distance restraints. We use fast-acting photolytic covalent labeling chemistries to probe surface topology (CL-MS) at high structural resolution. Our lab also pushes the boundaries in hydrogen-deuterium exchange mass spectrometry (HX-MS) for the detection of structure-function properties of large systems.