Cryo-EM reconstruction of continuous heterogeneity by Laplacian spectral volumes
- 27 January 2020
- journal article
- research article
- Published by IOP Publishing in Inverse Problems
- Vol. 36 (2), 024003
- https://doi.org/10.1088/1361-6420/ab4f55
Abstract
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.Keywords
Funding Information
- National Institute of General Medical Sciences (R01GM090200)
- Air Force Office of Scientific Research (FA9550-17-1-0291)
- Army Research Office (W911NF-17-1-0512)
- Simons Investigator Award
- The Moore Foundation Data-Driven Discovery Investigator Award
- NSF BIGDATA Award (IIS-1837992)
This publication has 61 references indexed in Scilit:
- Two-Dimensional Tomography from Noisy Projections Taken at Unknown Random DirectionsSIAM Journal on Imaging Sciences, 2013
- RELION: Implementation of a Bayesian approach to cryo-EM structure determinationJournal of Structural Biology, 2012
- Outcome of the First Electron Microscopy Validation Task Force MeetingStructure, 2012
- A Bayesian View on Cryo-EM Structure DeterminationJournal of Molecular Biology, 2012
- Identifying Conformational States of Macromolecules by Eigen-Analysis of Resampled Cryo-EM ImagesStructure, 2011
- Automated multi-model reconstruction from single-particle electron microscopy dataJournal of Structural Biology, 2010
- EMAN2: An extensible image processing suite for electron microscopyJournal of Structural Biology, 2006
- A method of focused classification, based on the bootstrap 3D variance analysis, and its application to EF-G-dependent translocationJournal of Structural Biology, 2006
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004