Single molecule x-ray scattering experiments using free-electron lasers hold the potential to resolve biomolecular structures and structural ensembles. However, molecular electron density determination has so far not been achieved because of low photon counts, high noise levels, and low hit rates. Most approaches therefore focus on large specimen like entire viruses, which scatter sufficiently many photons to allow orientation determination of each image. Small specimens like proteins, however, scatter too few photons for the molecular orientations to be determined. Here, we present a rigorous Bayesian approach to overcome these limitations, additionally taking into account intensity fluctuations, beam polarization, irregular detector shapes, incoherent scattering, and background scattering. We demonstrate using synthetic scattering images that electron density determination of small proteins is possible in this extreme high noise Poisson regime. Tests on published virus data achieved the detector-limited resolution of 9 nm, using only 0.01% of the available photons per image.
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