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Methods. 2016 May 1;100:61-7. doi: 10.1016/j.ymeth.2016.02.007. Epub 2016 Feb 13.

Continuous changes in structure mapped by manifold embedding of single-particle data in cryo-EM.

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Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, United States; Department of Biological Sciences, Columbia University, New York, NY 10027, United States. Electronic address:
Department of Physics, University of Wisconsin Milwaukee, 3135 N. Maryland Ave, Milwaukee, WI 53211, United States. Electronic address:


Cryo-electron microscopy, when combined with single-particle reconstruction, is a powerful method for studying macromolecular structure. Recent developments in detector technology have pushed the resolution into a range comparable to that of X-ray crystallography. However, cryo-EM is able to separate and thus recover the structure of each of several discrete structures present in the sample. For the more general case involving continuous structural changes, a novel technique employing manifold embedding has been recently demonstrated. Potentially, the entire work-cycle of a molecular machine may be observed as it passes through a continuum of states, and its free-energy landscape may be mapped out. This technique will be outlined and discussed in the context of its application to a large single-particle dataset of yeast ribosomes.


Classification; Heterogeneity; Machine learning; Molecular machines; Protein synthesis; Ribosome

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