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Exploiting prior knowledge about biological macromolecules in cryo-EM structure determination

By Dari Kimanius, Gustav Zickert, Takanori Nakane, Jonas Adler, Sebastian Lunz, Carola-Bibiane Schönlieb, Ozan Öktem, Sjors Scheres

Posted 26 Mar 2020
bioRxiv DOI: 10.1101/2020.03.25.007914

Three-dimensional reconstruction of the electron scattering potential of biological macromolecules from electron cryo-microscopy (cryo-EM) projection images is an ill-posed problem. The most popular cryo-EM software solutions to date rely on a regularisation approach that is based on the prior assumption that the scattering potential varies smoothly over three-dimensional space. Although this approach has been hugely successful in recent years, the amount of prior knowledge it exploits compares unfavourably to the knowledge about biological structures that has been accumulated over decades of research in Structural Biology. Here, we present a regularisation framework for cryo-EM structure determination that exploits prior knowledge about biological structures through a convolutional neural network that is trained on known macromolecular structures. We insert this neural network into the iterative cryo-EM structure determination process through an approach that is inspired by Regularisation by Denoising. We show that the new regularisation approach yields better reconstructions than the current state-of-the-art for simulated data and discuss options to extend this work for application to experimental cryo-EM data. ### Competing Interest Statement The authors have declared no competing interest.

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