In a flash of light: X-ray free electron lasers meet native mass spectrometry

During the last years, X-ray free electron lasers (XFELs) have emerged as X-ray sources of unparalleled brightness, delivering extreme amounts of photons in femtosecond pulses. As such, they have opened up completely new possibilities in drug discovery and structural biology, including studying high resolution biomolecular structures and their functioning in a time resolved manner, and diffractive imaging of single particles without the need for their crystallization. In this perspective, we briefly review the operation of XFELs, their immediate uses for drug discovery and focus on the potentially revolutionary single particle diffractive imaging technique and the challenges which remain to be overcome to fully realize its potential to provide high resolution structures without the need for crystallization, freezing or the need to keep proteins stable at extreme concentrations for long periods of time. As the issues have been to a large extent sample delivery related, we outline a way for native mass spectrometry to overcome these and enable so far impossible research with a potentially huge impact on structural biology and drug discovery, such as studying structures of transient intermediate species in viral life cycles or during functioning of molecular machines.