Novel mass analyzer unravels complex biomolecular structures

In Nature Methods the group of Albert Heck of Utrecht University introduces a new mass spectrometer based on Orbitrap™ technology. This high-sensitive instrument might play a crucial role in the development and use of therapeutic antibodies.

The Heck group, in close collaboration with the research group of Alexander Makarov of Thermo Fisher, the inventor of the Orbitrap analyzer, show that protein assemblies of molecular weights over 1 million Da can be analyzed with very high analytical resolving power and exquisite sensitivity down to detection of single ions. The new mass spectrometer allows the measurement of a range of important proteins and protein assemblies allowing a detailed analytical footprint of these biologically and medically important molecules. Especially in the fast-growing arena of biopharmaceuticals (e.g. therapeutic antibodies) this new instrument will be important both in research & development and in quality control, to enable such molecularly complex biomolecules to be used safely in the clinic.

Heck: “The impact of the high mass resolving power at very high sensitivity as achievable with this new mass spectrometer is tremendous; it opens up avenues to measure not only protein-protein interactions, but also covalent and non-covalent binding of small molecules to protein assemblies.

Wide-ranging applications may include the direct analysis of drug molecules binding to their targets, and the investigation of post-translational and chemical modifications (e.g. phosphorylation, glycosylation) on intact proteins and protein assemblies. I foresee that this instrument will become instrumental in the development and use of therapeutic antibodies, but also for instance in analyzing how drug molecules such as proteasome inhibitors do interact with their target, the proteasome”.

Makarov: “Presently Orbitrap mass spectrometry is probably the fastest growing mass spectrometric technique. Through this collaboration with Utrecht University we have opened up new avenues for the use of this mass analyzer. I always believed in the versatility of the Orbitrap analyzer, but am still amazed to see that we can now also mass analyze huge protein complexes, even whole viruses, with substantially improved resolving power and mass accuracy and sensitivity down to individual ions.”

This research was made possible by support of the Netherlands Proteomics Centre, and the EU-funded large scale facility PRIME-XS.