Using molecular simulation to model high-resolution cryo-EM reconstructions

Serdal Kirmizialtin, Justus Loerke, Elmar Behrmann, Christian M.T. Spahn, Karissa Y. Sanbonmatsu

    Research output: Contribution to journalArticle

    Abstract

    An explosion of new data from high-resolution cryo-electron microscopy (cryo-EM) studies has produced a large number of data sets for many species of ribosomes in various functional states over the past few years. While many methods exist to produce structural models for lower resolution cryo-EM reconstructions, high-resolution reconstructions are often modeled using crystallographic techniques and extensive manual intervention. Here, we present an automated fitting technique for high-resolution cryo-EM data sets that produces all-atom models highly consistent with the EM density. Using a molecular dynamics approach, atomic positions are optimized with a potential that includes the cross-correlation coefficient between the structural model and the cryo-EM electron density, as well as a biasing potential preserving the stereochemistry and secondary structure of the biomolecule. Specifically, we use a hybrid structure-based/ab initio molecular dynamics potential to extend molecular dynamics fitting. In addition, we find that simulated annealing integration, as opposed to straightforward molecular dynamics integration, significantly improves performance. We obtain atomistic models of the human ribosome consistent with high-resolution cryo-EM reconstructions of the human ribosome. Automated methods such as these have the potential to produce atomistic models for a large number of ribosome complexes simultaneously that can be subsequently refined manually.

    Original languageEnglish (US)
    Pages (from-to)497-514
    Number of pages18
    JournalMethods in Enzymology
    Volume558
    Issue number1
    DOIs
    StatePublished - Jan 1 2015

    Fingerprint

    Cryoelectron Microscopy
    Electron microscopy
    Molecular Dynamics Simulation
    Ribosomes
    Molecular dynamics
    Structural Models
    Stereochemistry
    Explosions
    Biomolecules
    Simulated annealing
    Carrier concentration
    Electrons
    Atoms

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology

    Cite this

    Kirmizialtin, S., Loerke, J., Behrmann, E., Spahn, C. M. T., & Sanbonmatsu, K. Y. (2015). Using molecular simulation to model high-resolution cryo-EM reconstructions. Methods in Enzymology, 558(1), 497-514. https://doi.org/10.1016/bs.mie.2015.02.011

    Using molecular simulation to model high-resolution cryo-EM reconstructions. / Kirmizialtin, Serdal; Loerke, Justus; Behrmann, Elmar; Spahn, Christian M.T.; Sanbonmatsu, Karissa Y.

    In: Methods in Enzymology, Vol. 558, No. 1, 01.01.2015, p. 497-514.

    Research output: Contribution to journalArticle

    Kirmizialtin, S, Loerke, J, Behrmann, E, Spahn, CMT & Sanbonmatsu, KY 2015, 'Using molecular simulation to model high-resolution cryo-EM reconstructions', Methods in Enzymology, vol. 558, no. 1, pp. 497-514. https://doi.org/10.1016/bs.mie.2015.02.011
    Kirmizialtin S, Loerke J, Behrmann E, Spahn CMT, Sanbonmatsu KY. Using molecular simulation to model high-resolution cryo-EM reconstructions. Methods in Enzymology. 2015 Jan 1;558(1):497-514. https://doi.org/10.1016/bs.mie.2015.02.011
    Kirmizialtin, Serdal ; Loerke, Justus ; Behrmann, Elmar ; Spahn, Christian M.T. ; Sanbonmatsu, Karissa Y. / Using molecular simulation to model high-resolution cryo-EM reconstructions. In: Methods in Enzymology. 2015 ; Vol. 558, No. 1. pp. 497-514.
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