High-resolution mass spectrometry of small molecules bound to membrane proteins

A high-resolution, Orbitrap-based, native mass spectrometry approach allows the direct characterization of lipid, peptide and drug binding to intact membrane proteins. Small molecules are known to stabilize membrane proteins and to modulate their function and oligomeric state, but such interactions are often hard to precisely define. Here we develop and apply a high-resolution, Orbitrap mass spectrometry–based method for analyzing intact membrane protein–ligand complexes. Using this platform, we resolve the complexity of multiple binding events, quantify small molecule binding and reveal selectivity for endogenous lipids that differ only in acyl chain length.