ACE-HetEM for ab initio Heterogenous Cryo-EM 3D Reconstruction

Due to the extremely low signal-to-noise ratio (SNR) and unknown poses (projection angles and image translation) in cryo-EM experiments, reconstructing 3D structures from 2D images is very challenging. On top of these challenges, heterogeneous cryo-EM reconstruction also has an additional requirement: conformation classification. An emerging solution to this problem is called amortized inference, implemented using the autoencoder architecture or its variants. Instead of searching for the correct image-to-pose/conformation mapping for every image in the dataset as in non-amortized methods, amortized inference only needs to train an encoder that maps images to appropriate latent spaces representing poses or conformations. Unfortunately, standard amortized-inference-based methods with entangled latent spaces have difficulty learning the distribution of conformations and poses from cryo-EM images. In this paper, we propose an unsupervised deep learning architecture called "ACE-HetEM" based on amortized inference. To explicitly enforce the disentanglement of conformation classifications and pose estimations, we designed two alternating training tasks in our method: image-to-image task and pose-to-pose task. Results on simulated datasets show that ACE-HetEM has comparable accuracy in pose estimation and produces even better reconstruction resolution than non-amortized methods. Furthermore, we show that ACE-HetEM is also applicable to real experimental datasets.