Fall 2026 | Chemistry Seminar Series
"Chemical Rulers for Dynamic Proteins: Cross-Linking and Gas-Phase Reactivity in Structural Mass Spectrometry"
Dr. Ian Webb
Associate Professor, Department of Chemistry, Indiana University Indianapolis
Thursday, November 5th, 3:30pm in FB-253
Abstract: Most of what we know about protein structure comes from proteins that hold still. Much of the proteome does not. Intrinsically disordered proteins like a-synuclein, which accumulates in Parkinson’s disease, interconvert among many conformations, and that ensemble shifts with chemical modification and with the solution around it. Our lab designs mass spectrometry experiments that use chemical reactivity itself as a structural ruler. In solution the ruler is cross-linking: reagents of defined length covalently join two residues only when they are close, so a peptide mass becomes a distance constraint. On a membrane-mimetic micelle surface, unmodified and Ser129-phosphorylated a-synuclein engage differently. The unmodified protein folds its acidic C-terminal tail back against the membrane-bound helix; the phosphorylated form releases that tail and instead draws in the central aggregation-prone region. Yet in a strongly compacting osmolyte the two become indistinguishable. Phosphorylation imposes no fixed structure. It changes how the protein answers its chemical environment, and the environment can erase or amplify the difference. In the gas phase the ruler is ion–molecule chemistry. Protein ions unfold when heated by collisions, normally followed by ion mobility as a change in size. We instead react activated ions with ND3 and measure deuterium uptake and proton transfer, which report site accessibility and charge solvation rather than overall shape, on instruments with no mobility cell. This readout also separates the two a-synuclein proteoforms, and detects lost stability in a therapeutic antibody after deglycosylation.