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

Senik Matinyan¹ Pavel Filipcik¹ Eric Van Genderen² Jan Pieter Abrahams^{1, 2*}

• ¹Biozentrum, Basel University, Switzerland
• ²Paul Scherrer Institut (PSI), Switzerland

Introduction. Proteins that adopt multiple conformations pose significant challenges in structural biology research and pharmaceutical development, as structure determination via single particle cryoelectron 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.Methods. 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.Results. For simulated datasets, DiffraGAN allows effectively determining protein structures at atomic resolution from diffraction patterns and noisy low-resolution images.Discussion. 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.