title: Modeling experimental image formation for likelihood-based classification of electron microscopy data.
abstract: The coexistence of multiple distinct structural states often obstructs the application of three-dimensional cryo-electron microscopy to large macromolecular complexes. Maximum likelihood approaches are emerging as robust tools for solving the image classification problems that are posed by such samples. Here, we propose a statistical data model that allows for a description of the experimental image formation within the formulation of 2D and 3D maximum-likelihood refinement. The proposed approach comprises a formulation of the probability calculations in Fourier space, including a spatial frequency-dependent noise model and a description of defocus-dependent imaging effects. The Expectation-Maximization-like algorithms presented are generally applicable to the alignment and classification of structurally heterogeneous projection data. Their effectiveness is demonstrated with various examples, including 2D classification of top views of the archaeal helicase MCM and 3D classification of 70S E. coli ribosome and Simian Virus 40 large T-antigen projections.
authors.affiliation: Centro Nacional de Biotecnología CSIC, Cantoblanco, 28049, Madrid, Spain.
authors.forename: Sjors H W
authors.initials: SH
authors.lastname: Scheres
authors.forename: Rafael
authors.initials: R
authors.lastname: Núñez-Ramírez
authors.forename: Yacob
authors.initials: Y
authors.lastname: Gómez-Llorente
authors.forename: Carmen
authors.initials: C
authors.lastname: San Martín
authors.forename: Paul P B
authors.initials: PP
authors.lastname: Eggermont
authors.forename: José María
authors.initials: JM
authors.lastname: Carazo
mesh_terms: D000465:Algorithms; D000952:Antigens, Polyomavirus Transforming / Q000737:chemistry* / Q000648:ultrastructure; D019843:Archaeal Proteins / Q000737:chemistry* / Q000648:ultrastructure; D020285:Cryoelectron Microscopy / Q000379:methods* / Q000706:statistics & numerical data; D004265:DNA Helicases / Q000737:chemistry* / Q000648:ultrastructure; D004926:Escherichia coli / Q000378:metabolism; D021621:Imaging, Three-Dimensional; D016013:Likelihood Functions; D008958:Models, Molecular; D015233:Models, Statistical; D011487:Protein Conformation; D012270:Ribosomes / Q000737:chemistry* / Q000648:ultrastructure
chemical_list: D000952:Antigens, Polyomavirus Transforming; D019843:Archaeal Proteins; D004265:DNA Helicases; C403162:MCM protein, Methanobacterium thermoautotrophicum