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

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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

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, 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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