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Aerosol delivery-based serial femtosecond crystallography

Kim, Y.; Koua, F. H. M.; de Wijn, R.; Worbs, L.; Schubert, R.; Kantamneni, S.; E, J.; Sobolev, E.; Melo, D.; Turkot, O.; Wrona, A.; Kloos, M.; Wei, C.; Xie, Q.; Round, A.; Koliyadu, J.; Sikorski, M.; Letrun, R.; Doerner, K.; Han, H.; Schulz, J.; Mancuso, A. P.; Sato, T.; Bean, R.; Bielecki, J.; Kim, C.

2026-04-24 biophysics
10.64898/2026.04.21.719866 bioRxiv
Show abstract

Serial femtosecond crystallography (SFX) has revolutionised structural biology by enabling direct visualization of conformational dynamics of biomacromolecules at near-physiological temperatures. However, conventional SFX sample delivery at X-ray free-electron laser (XFEL) facilities introduces a significant X-ray scattering background, which may limit the data quality and resolution. Here, we introduce an aerosol delivery-based method that drastically reduces the back-ground scattering by minimising the liquid environment surrounding the nanocrystals. We validate our method by solving the structure of Cydia pomonella granulovirus nanocrystals at 1.9 [A] resolution, achieving orders-of-magnitude lower background scattering compared to a liquid jet-based method. Structural comparison with the liquid jet-based model revealed similar overall structure, suggesting that the native structure is largely preserved despite dehydration during aerosolisation. Our method enables efficient SFX studies, particularly pump-probe time-resolved SFX on protein nanocrystals with enhanced signal-to-noise ratios, as well as high-throughput small molecule SFX (smSFX) applications for pharmaceuticals and functional materials.

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