“…In proteins, the chemistry of modification is well-established, and many types of side chain can be efficiently labeled and the products easily detected by mass spectrometry, although the dynamic range of labeling varies considerably, with aromatic and sulfur containing side chains easily labeled and aliphatic and polar residues labeled less efficiently (15,16). For soluble proteins, it is well-established that this intrinsic reactivity and the solvent accessibility of the side chains govern their observed reactivity (15,17,18). For membrane proteins, these approaches have not been previously explored, such that it was unclear what factors would govern labeling, or whether the overall scavenging effects of detergents or lipids are limiting.…”