Strategies for processing diffraction data from randomly oriented particles

The high intensity of free-electron X-ray light sources may enable structure determinations of viruses or even individual proteins without the encumbrance of first forming crystals. This note compares two schemes of non-crystalline diffraction data collection that have been proposed: serial single-shot data from individual particles, and averaged cross-correlation data from particle ensembles. The information content of these schemes is easily compared and we show that the single-shot approach, although experimentally more challenging, is always superior in this respect. In fact, for 3D structure determination a constraint counting argument shows that the cross-correlation scheme suffers from data deficiency.