Advances in Mass Spectrometry‐Based Structural Proteomics: Development of HDX‐MS and XL‐MS Techniques from Recombinant Protein to Cellular Systems

Abstract Mass spectrometry (MS) is a central analytical technique used to study proteins and biomolecules. It measures mass‐to‐charge ratio of ions to identify and quantify molecules in simple and complex mixtures. Technological advancement in instrumentation, sample preparation methodologies, and data analysis workflows continue to push the capabilities of MS to answer more complicated questions and vice versa. Structural proteomics uses MS‐based methodologies to characterize protein structure. Specifically, but not limited to, hydrogen deuterium exchange MS (HDX‐MS) and crosslinking MS (XL‐MS) are complementary techniques that capture the structural plasticity inherent to proteins in solution. This review is intended to present recent progress in HDX‐MS and XL‐MS that have allowed these techniques to be used not only for simple recombinant protein systems but with complex cellular systems.