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Mass spectrometers are weighing meters of molecules. In conventional electrospray ionization mass spectrometry (ESI-MS), solvated ions are transferred to the gas phase through rapid evaporation at the front end (source region) of the instrument, with the high temperature being a key driving force. This often is the cause of the loss of non-covalent interactions during the ESI process. Hence, detecting non-covalently bound macromolecular protein complexes through conventional mass spectral approaches has remained a challenge.


In native MS, we overcome this using a combination of strategies. At the front end of the instrument, we employ an offline nano-ESI source which decreases the flowrate of the ESI sample spray by orders of magnitude. This allows the ES process to take place at an ambient temperature, which in turn enables us to maintain the non-covalent interactions. In conjunction, we employ a higher pressure, termed as backing pressure, at the source region of the instrument. This process, termed as collisional cooling, provides a route to reduce the kinetic energies of macromolecules and streamline their motion in the gas phase. This non-evasive way of performing ESI-MS that aims to maintain both covalent, as well as non-covalent, ‘native’ chemical contacts between biomolecules is termed as native MS. This enables us to detect and analyze macromolecular protein complexes as big and complex as the entire ribosome.


Using nativeMS, in combination with a range of orthogonal biophysical, cell biology, imaging, and computational approaches we aim to understand how macromolecular protein complexes formed at the cellular membrane regulate cellular signaling. 

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