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Abstract Single-particle cryogenic electron microscopy (cryo-EM) is an imaging technique capable of recovering the high-resolution three-dimensional (3D) structure of biological macromolecules from many noisy and randomly oriented projection images. One notable approach to 3D reconstruction, known as Kam’s method, relies on the moments of the two-dimensional (2D) images. Inspired by Kam’s method, we introduce a rotationally invariant metric between two molecular structures, which does not require 3D alignment. Further, we introduce a metric between a stack of projection images and a molecular structure, which is invariant to rotations and reflections and does not require performing 3D reconstruction. Additionally, the latter metric does not assume a uniform distribution of viewing angles. We demonstrate the uses of the new metrics on synthetic and experimental datasets, highlighting their ability to measure structural similarity. 

The number of noisy images required for molecular reconstruction in single-particle cryoelectron microscopy (cryo-EM) is governed by the autocorrelations of the observed, randomly oriented, noisy projection images. In this work, we consider the effect of imposing sparsity priors on the molecule. We use techniques from signal processing, optimization, and applied algebraic geometry to obtain theoretical and computational contributions for this challenging nonlinear inverse problem with sparsity constraints. We prove that molecular structures modeled as sums of Gaussians are uniquely determined by the second-order autocorrelation of their projection images, implying that the sample complexity is proportional to the square of the variance of the noise. This theory improves upon the nonsparse case, where the third-order autocorrelation is required for uniformly oriented particle images and the sample complexity scales with the cube of the noise variance. Furthermore, we build a computational framework to reconstruct molecular structures which are sparse in the wavelet basis. This method combines the sparse representation for the molecule with projection-based techniques used for phase retrieval in X-ray crystallography. 

Single-Particle Reconstruction (SPR) in Cryo-Electron Microscopy (cryo-EM) is the task of estimating the 3D structure of a molecule from a set of noisy 2D projections, taken from unknown viewing directions. Many algorithms for SPR start from an initial reference molecule, and alternate between refining the estimated viewing angles given the molecule, and refining the molecule given the viewing angles. This scheme is called iterative refinement. Reliance on an initial, user-chosen reference introduces model bias, and poor initialization can lead to slow convergence. Furthermore, since no ground truth is available for an unsolved molecule, it is difficult to validate the obtained results. This creates the need for high quality ab initio models that can be quickly obtained from experimental data with minimal priors, and which can also be used for validation. We propose a procedure to obtain such an ab initio model directly from raw data using Kam's autocorrelation method. Kam's method has been known since 1980, but it leads to an underdetermined system, with missing orthogonal matrices. Until now, this system has been solved only for special cases, such as highly symmetric molecules or molecules for which a homologous structure was already available. In this paper, we show that knowledge of just two clean projections is sufficient to guarantee a unique solution to the system. This system is solved by an optimization-based heuristic. For the first time, we are then able to obtain a low-resolution ab initio model of an asymmetric molecule directly from raw data, without 2D class averaging and without tilting. Numerical results are presented on both synthetic and experimental data.