Our principal research goal is to develop mass spectrometry (MS) instrumentation and methods for protein biophysics and structural proteomics. We wish to understand protein folding, to determine ligand binding sites, to quantify protein/ligand interactions, and to determine protein interfaces especially for systems involved in protein misfolding. Our goal is a "tool box" of various methods involving covalent footprinting of proteins (e.g., H/D amide exchange, reactive radical footprinting, and specific chemical reactions). We currently emphasize H/D exchange of proteins, as monitored by ESI, as an approach to understanding protein folding and interactions.  We extended this by building a new method (PLIMSTEX) in which we use exchange and modeling to determine protein/ligand interactions. We also are investigating the reactions of OH and other radicals, generated with a short laser pulse, with proteins as a structural tool that is complementary to H/D exchange . We seek to discover new reactions for protein footprinting and to test applicability in problem solving. The instrumentation we use for this research are a Quadrupole/Time-of-Flight mass spectrometer, a 12-tesla FT-Ion Cyclotron Resonance mass spectrometer, an Orbitrap, and two 7-tesla FT ICR mass spectrometers. Analysis is by both "bottom-up" and "top-down" MS-based proteomics utilizing electrospray ionization, native spray, and high resolving power mass analyzers.  We are also interested in developing Fourier transform mass spectrometry by implementing new ion-trapping methods and electrically compensated cells to afford improvements in mass resolving power, mass measurement, and ability to store, manipulate, and react biomolecule ions and reactive species. Our laboratory is also a NIH research resource commissioned to provide collaboration and service in mass spectrometry including molecular weight measurement, accurate mass measurement, tandem mass spectrometry experiments, and proteomics. We seek collaborations particularly in the area of biophysical properties of proteins and top-down protein sequencing.