Publication

Joint Angular Refinement and Reconstruction for Single-Particle Cryo-EM

Abstract

Single-particle cryo-electron microscopy (cryo-EM) reconstructs the three-dimensional (3D) structure of bio-molecules from a large set of 2D projection images with random and unknown orientations. A crucial step in the single-particle cryo-EM pipeline is 3D refinement, which resolves a high-resolution 3D structure from an initial approximate volume by refining the estimation of the orientation of each projection. In this work, we propose a new approach that refines the projection angles on the continuum. We formulate the optimization problem over the density map and the orientations jointly. The density map is updated using the efficient alternating-direction method of multipliers, while the orientations are updated through a semi-coordinate-wise gradient descent for which we provide an explicit derivation of the gradient. Our method eliminates the requirement for a fine discretization of the orientation space and does away with the classical but computationally expensive template-matching step. Numerical results demonstrate the feasibility and performance of our approach compared to several baselines.

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Related concepts (33)
Cryogenic electron microscopy
Cryogenic electron microscopy (cryo-EM) is a cryomicroscopy technique applied on samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An aqueous sample solution is applied to a grid-mesh and plunge-frozen in liquid ethane or a mixture of liquid ethane and propane. While development of the technique began in the 1970s, recent advances in detector technology and software algorithms have allowed for the determination of biomolecular structures at near-atomic resolution.
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Transmission electron cryomicroscopy (CryoTEM), commonly known as cryo-EM, is a form of cryogenic electron microscopy, more specifically a type of transmission electron microscopy (TEM) where the sample is studied at cryogenic temperatures (generally liquid-nitrogen temperatures). Cryo-EM is gaining popularity in structural biology. The utility of transmission electron cryomicroscopy stems from the fact that it allows the observation of specimens that have not been stained or fixed in any way, showing them in their native environment.
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Single particle analysis is a group of related computerized image processing techniques used to analyze images from transmission electron microscopy (TEM). These methods were developed to improve and extend the information obtainable from TEM images of particulate samples, typically proteins or other large biological entities such as viruses. Individual images of stained or unstained particles are very noisy, and so hard to interpret. Combining several digitized images of similar particles together gives an image with stronger and more easily interpretable features.
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