NiuEM: A Nested-iterative Unsupervised Learning Model for Single-particle Cryo-EM Image Processing

Cryo-electron microscopy (cryo-EM) has become a mainstream technology for solving spatial structures of biomacromolecules, while the processing of cryo-EM images is a very challenging task. One of the great challenges is the high noise in the images. A common method is to cluster the images with close projecting angles to get mean images, which are used for 3D reconstruction. However, due to the extremely low signal-to-noise-ratio, common clustering methods often fail to obtain high-quality mean images, leading to poorly reconstructed structures. In this study, we present a new unsupervised learning framework, called NiuEM, to discriminate images captured from different angles and yield cluster-mean images. NiuEM first generates pseudo-labels and then exploits both contrastive loss and cross-entropy loss for training convolutional layers to learn feature representations. Moreover, the pseudo-labels are updated iteratively to enhance the reliability of labels. We assess the performance of NiuEM on four data sets via both visualized and quantitative experiments. Especially, two kinds of metrics are adopted to measure the performance, regarding the clustering quality and the resolution of reconstructed 3D models, respectively. The experimental results show that NiuEM achieves very competitive clustering accuracy in the comparison with the state-of-the-art image clustering methods. Moreover, the cluster mean images yielded by NiuEM lead to better initial 3D models compared with the mainstream reconstruction tools.