title: A Bayesian view on cryo-EM structure determination.
abstract: Three-dimensional (3D) structure determination by single-particle analysis of cryo-electron microscopy (cryo-EM) images requires many parameters to be determined from extremely noisy data. This makes the method prone to overfitting, that is, when structures describe noise rather than signal, in particular near their resolution limit where noise levels are highest. Cryo-EM structures are typically filtered using ad hoc procedures to prevent overfitting, but the tuning of arbitrary parameters may lead to subjectivity in the results. I describe a Bayesian interpretation of cryo-EM structure determination, where smoothness in the reconstructed density is imposed through a Gaussian prior in the Fourier domain. The statistical framework dictates how data and prior knowledge should be combined, so that the optimal 3D linear filter is obtained without the need for arbitrariness and objective resolution estimates may be obtained. Application to experimental data indicates that the statistical approach yields more reliable structures than existing methods and is capable of detecting smaller classes in data sets that contain multiple different structures.
authors.affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK. scheres@mrc-lmb.cam.ac.uk
authors.forename: Sjors H W
authors.initials: SH
authors.lastname: Scheres
mesh_terms: D020285:Cryoelectron Microscopy / Q000379:methods*; D021621:Imaging, Three-Dimensional / Q000379:methods*; D046911:Macromolecular Substances / Q000648:ultrastructure*; D015233:Models, Statistical; D052638:Particulate Matter
chemical_list: D046911:Macromolecular Substances; D052638:Particulate Matter
references.citation: J Struct Biol. 1999 Dec 1;128(1):82-97
references.pmid: 10600563
references.citation: J Struct Biol. 2011 Oct;176(1):60-74
references.pmid: 21757012
references.citation: J Biol Chem. 2003 Nov 7;278(45):44959-65
references.pmid: 12920124
references.citation: J Struct Biol. 2006 Sep;155(3):470-81
references.pmid: 16762565
references.citation: Magn Reson Med. 1999 Jan;41(1):179-86
references.pmid: 10025627
references.citation: Structure. 2007 Oct;15(10):1167-77
references.pmid: 17937907
references.citation: J Struct Biol. 2005 Jul;151(1):41-60
references.pmid: 15890530
references.citation: J Struct Biol. 2002 Apr-May;138(1-2):34-46
references.pmid: 12160699
references.citation: Curr Opin Struct Biol. 2011 Apr;21(2):265-73
references.pmid: 21333526
references.citation: J Struct Biol. 2004 Nov;148(2):194-204
references.pmid: 15477099
references.citation: Nature. 2009 Sep 10;461(7261):292-5
references.pmid: 19718020
references.citation: Methods Enzymol. 2010;482:35-72
references.pmid: 20888957
references.citation: Proc IEEE Int Symp Biomed Imaging. 2010 Apr 14;2010:169-172
references.pmid: 20729994
references.citation: Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
references.pmid: 15299926
references.citation: J Struct Biol. 2009 May;166(2):126-32
references.pmid: 19269332
references.citation: Adv Protein Chem Struct Biol. 2010;81:89-119
references.pmid: 21115174
references.citation: J Struct Biol. 2008 Apr;162(1):108-20
references.pmid: 18166488
references.citation: Q Rev Biophys. 2011 Aug;44(3):357-90
references.pmid: 21524337
references.citation: Methods Enzymol. 2010;482:263-94
references.pmid: 20888965
references.citation: J Mol Biol. 2003 Oct 31;333(4):721-45
references.pmid: 14568533
references.citation: J Struct Biol. 2007 Jan;157(1):117-25
references.pmid: 16828314
references.citation: J Mol Biol. 1998 Apr 17;277(5):1033-46
references.pmid: 9571020
references.citation: Methods Enzymol. 2010;481:343-69
references.pmid: 20887864
references.citation: Methods Enzymol. 2010;482:211-35
references.pmid: 20888963
references.citation: Nat Protoc. 2008;3(6):977-90
references.pmid: 18536645
references.citation: Methods Enzymol. 1997;277:366-96
references.pmid: 18488318
references.citation: Ultramicroscopy. 2004 Dec;102(1):67-84
references.pmid: 15556702
references.citation: Structure. 2010 Jul 14;18(7):777-86
references.pmid: 20637414
references.citation: J Struct Biol. 2010 Apr;170(1):98-108
references.pmid: 20085819
references.citation: Methods Enzymol. 2010;482:295-320
references.pmid: 20888966
references.citation: Methods Enzymol. 2010;481:xv-xvi
references.pmid: 20887849
references.citation: Q Rev Biophys. 2004 Feb;37(1):3-13
references.pmid: 17390603
references.citation: Bioinformatics. 2010 Oct 1;26(19):2406-15
references.pmid: 20702397
references.citation: J Struct Biol. 2007 Jan;157(1):281-7
references.pmid: 16963278
references.citation: Science. 2005 Jul 8;309(5732):303-6
references.pmid: 16002620