DiffraGAN: a conditional generative adversarial network for phasing single molecule diffraction data to atomic resolution

Proteins that adopt multiple conformations pose significant challenges in structural biology research and pharmaceutical development, as structure determination via single particle cryo-electron microscopy (cryo-EM) is often impeded by data heterogeneity. In this context, the enhanced signal-to-noise ratio of single molecule cryo-electron diffraction (simED) offers a promising alternative. However, a significant challenge in diffraction methods is the loss of phase information, which is crucial for accurate structure determination. Here, we present DiffraGAN, a conditional generative adversarial network (cGAN) that estimates the missing phases at high resolution from a combination of single particle high-resolution diffraction data and low-resolution image data. For simulated datasets, DiffraGAN allows effectively determining protein structures at atomic resolution from diffraction patterns and noisy low-resolution images. Our findings suggest that combining single particle cryo-electron diffraction with advanced generative modeling, as in DiffraGAN, could revolutionize the way protein structures are determined, offering an alternative and complementary approach to existing methods.