2020Moscovich DiffusionMaps

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A. Moscovich, A. Halevi, J. Andén, A. Singer, "Cryo-EM reconstruction of continuous heterogeneity by Laplacian spectral volumes", Inverse Problems, 36 (2) 024003 (2020).


Single-particle electron cryomicroscopy is an essential tool for high-resolution 3D reconstruction of proteins and other biological macromolecules. An important challenge in cryo-EM is the reconstruction of non-rigid molecules with parts that move and deform. Traditional reconstruction methods fail in these cases, resulting in smeared reconstructions of the moving parts. This poses a major obstacle for structural biologists, who need high-resolution reconstructions of entire macromolecules, moving parts included. To address this challenge, we present a new method for the reconstruction of macromolecules exhibiting continuous heterogeneity. The proposed method uses projection images from multiple viewing directions to construct a graph Laplacian through which the manifold of three-dimensional conformations is analyzed. The 3D molecular structures are then expanded in a basis of Laplacian eigenvectors, using a novel generalized tomographic reconstruction algorithm to compute the expansion coefficients. These coefficients, which we name spectral volumes, provide a high-resolution visualization of the molecular dynamics. We provide a theoretical analysis and evaluate the method empirically on several simulated data sets.


Single particle electron cryomicroscopy, heterogeneity, tomographic reconstruction, molecular conformation space, manifold learning, Laplacian eigenmaps, diffusion maps



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